IL207315A - Piperidine derivative - Google Patents
Piperidine derivativeInfo
- Publication number
- IL207315A IL207315A IL207315A IL20731510A IL207315A IL 207315 A IL207315 A IL 207315A IL 207315 A IL207315 A IL 207315A IL 20731510 A IL20731510 A IL 20731510A IL 207315 A IL207315 A IL 207315A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- thiabenzo
- dihydro
- ylidene
- azulen
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
PIPERIDINE DERIVATIVE
NIPPON ZO 1 PHARMACEUTICAL CO., LTD.
DESCRIPTION
PIPERIDINE DERIVATIVE
TECHNICAL FIELD
[0001] The present invention relates to a piperidine derivative and salt and hydrate thereof that are pharmaceutically acceptable, which are useful as pharmaceutical compositions, particularly active ingredients such as antihistamines.
BACKGROUND ART
[0002] Histamines are representative chemical mediators that induce
allergic reactions, and the histamines are released from cells such as mast cells and basophils when substances that are causative of allergy are entered into the body. The released histamines are bound to a histamine type 1 receptor (H I receptor) protein to exhibit pharmacological actions such as hypotension, vascular hyperpermeability, constriction of smooth muscles, vasodilatation, or glandular hypersecretion, and involved in the manifestation of allergic reactions and inflammations. As described above, histamines are related to various diseases of human, and the allergic diseases and inflammations can be prevented or cured by controlling their actions. Agents for controlling histamine release and agents for inhibiting the binding of histamines with receptors (antihistamines) are numerously commercially available, and the agents are used in diseases such as bronchial asthma, allergic rhinitis, pollinosis, urticaria, and atopic
dermatitis.
[0003] However, antihistamines that are conventionally known exhibit some undesired side effects such as sedative action, drowsiness, dizziness, and malaise, based on the actions on the central nervous system; and dry mouth, mucosal dryness, and visual impairment, based on the anticholinergic actions; therefore, there are some limitations of use such as prohibition of taking antihistamines before driving automobiles, which in turn cause inconvenience in use. For these reasons, antihistamines which are free from such problems and have excellent effects are in demand from the patients and the medical sites. The present inventors have found a piperidine derivative of the present invention having smaller side effects o the central nervous system and potent antihistamine action.
[0004] Piperidine derivatives having a thiabenzo azulene backbone are disclosed in Patent Publications 1 to 13, among which those that are disclosed in Patent Publications 1 to 7 are compounds that are different from the compound of the present invention, in that both of Ri and R2 in the following general formula (I) are a hydrogen. In addition, Patent Publication 8 discloses a compound where R] in the following general formula (I) is an alkyl which may be substituted by an acyl or a hydroxy, and R2 is a hydrogen or a chlorine. Patent Publications 9 to 13 disclose compounds where R| is a hydrogen, and R2 is a halogen, an alkyl, or an alkoxy in the following general formula (I), However, Patent Publication
8 discloses that the compound has sedative action, and Patent Publication
9 discloses that a compound has antagonistic actions for ptosis and catalepsy, and suppressive actions for abnormal drop in body temperature
and tremors, respectively. In addition, the compounds disclosed in Patent Publications 10 to 13 are described to possess antihistamine action, but do not disclose on the amelioration on the side effects on the central nervous system, such as drowsiness, which is a side reaction of conventional antihistamines, as in the compounds of the present invention. For example, ketotifen fumarate disclosed in Patent Publication 10 is widely used as a second generation antihistamine, it is a matter to be remarked upon use on the side reactions that induced drowsiness. As described above, no reports have been so far made on piperidine derivatives having a thiabenzo azulene backbone having smaller side effects on the central nervous system and potent antihistamine actions as in the compounds of the present invention.
Patent Publication 1 : Japanese Patent Laid-Open No. Hei-3-294277 Patent Publication 2: Japanese Unexamined Patent Publication No. 2001 -5 19789
Patent Publication 3: Japanese Unexamined Patent Publication No. Hei-6-504992
Patent Publication 4: Japanese Patent Laid-Open No. Hei- 1 - 104069 Patent Publication 5: Japanese Patent Laid-Open No. Sho-57-77673 Patent Publication 6: Japanese Examined Patent Publication No. Sho-57-60351
Patent Publication 7: Japanese Unexamined Patent Publication No. Hei-3-504855
Patent Publication 8: Japanese Patent Laid-Open No. Sho-49-69677 Patent Publication 9: Japanese Patent Laid-Open No. Sho-51 - 1 10572
Patent Publication 10: Japanese Examined Patent Publication No. Sho-52- 17030
Patent Publication 1 1 : Japanese Examined Patent Publication No. Sho-55-8984
Patent Publication 12: Japanese Patent Laid-Open No. Sho-48-81869 Patent Publication 13: French Patent No. 1,437,412
DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION
[0006] An object of the present invention is to provide a pharmaceutical composition that has smaller side effects in the central nervous system, such as drowsiness, and excellent action, particularly a useful compound as an active ingredient such as an antihistamine.
MEANS TO SOLVE THE PROBLEMS
[0007] As a result of intensive studies on antihistamine compounds having the characteristics mentioned above, the present inventors have found that a piperidine derivative represented by the structural formula (I) given below is a compound useful as a medicament that has excellent
antihistamine action and alleviates side effects in the central nervous system, such as drowsiness. The present invention has been perfected thereby.
EFFECTS OF THE INVENTION
[0008] The piperidine derivative of the present invention has an excellent
antagonistic action for histamine receptors and shows low brain transfer even in a cerebral receptor binding test where a mouse is orally
administered with the compound, and consequently exhibits an effect of alleviating side effects in the central nervous system, such as drowsiness. Therefore, the piperidine derivative has properties desired for active ingredients of pharmaceutical compositions such as antihistamines, and is highly useful.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention relates to a piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable, wherein the piperidine derivative is represented by the following general formula (I):
wherein Rj stands for a hydrogen or a substituent selected from the following (a) to (j):
(a) a halogen,
(b) a cyano,
(c) acrylic acid (including an alkyl ester and a hydroxyalkylamide),
(d) a ureido,
(e) an alkenyl,
(f) an aminoalkyl which may be substituted with an alkylcarbonyl or an aminocarbonyl,
(g) a carbonylalkyi substituted with a hydroxy, an alkoxy or a
hydroxyalkylamino,
(h) a carbonyl substituted with a hydroxy, a morpholino, an alkoxy, a hydroxyalkylaminoalkoxy or cyclohexyloxycarbonyloxyalkoxy,
(i) a carbonylamino substituted with an alkyl or an alkoxy,
(j) an aminocarbonyl which may be substituted with one or two
substituents selected from an amino, a hydroxy, an alkoxy, an alkenyl, and an alkyl (which may be substituted with a halogen, a thiol, a piperidino, an amino, an alkoxy, an alkoxycarbonyl, an aminocarbonyl, or one or two hydroxys);
R2 stands for a hydrogen or a substituent selected from the following (k) to
(s):
(k) a cyano,
(1) acrylic acid (including an alkyl ester and a hydroxyalkylamide), (m) an alkyl which may be substituted with a hydroxy or a piperidino, (n) a carbonylalkyi substituted with a hydroxy, an alkoxy (which may be substituted with a cyclohexyloxycarbonyloxy), a piperidino, or a hydroxyalkylamino,
(o) a carbonyl substituted with a hydroxy, an alkoxy, or a
hydroxyalkylamino,
(p) a carbonylalkoxy substituted with a hydroxy or an alkoxy,
(q) a carbonylalkylsulfanyl substituted with a hydroxy or an alkoxy, (r) an alkoxy,
(s) a halogen; and
R3 stands for a hydrogen or a substituent selected from the following (t) to (x):
(t) an alkyl which may be substituted with a carboxy, a cyano, a
pyrrolidyl, a piperidino, an alkoxy, an alkylsulfanyl, or one or two hydroxys,
(u) a carbonyl substituted with an alkyl or alkoxy,
(v) a carbonylalkoxyalkyl substituted with a hydroxy or an alkoxy, (w) a carbonylalkyl substituted with an alkyl, an alkoxy, or an
alkylphenyl,
(x) an aminoalkyl substituted with an aminocarbonyl or an
alkanesulfonyl,
wherein one of the above R] and R2 stands for a substituent other than a hydrogen, A stands for unsubstituted or an oxo, B stands for a carbon or an oxygen, one of X and Y stands for a carbon and the other stands for a sulfur, a broken line part stands for a single bond or a double bond, with proviso that when R2 stands for a halogen or an alkoxy, A is unsubstituted, Ri stands for a substituent other than a hydrogen, and B stands for an oxygen.
] In the above-mentioned general formula (I), the term "alkyl"
(including the "alkyl" in an alkyl ester, an alkylphenyl, a
hydroxyalkylamide, a hydroxyalkylamino, an alkylcarbonyl, an
aminoalkyl, a carbonylalkyl, a hydroxyalkylaminoalkoxy, a
hydroxyalkylamino, a carbonylalkoxyalkyl, an alkylsulfanyl, and a carbonylalkylsulfanyl) stands for a linear or branched alkyl group having 1
to 6 carbon atoms, and the alkyl group is preferably, for example, a methyl, an ethyl, a propyl, an isopropyl, a butyl, an isobutyl, a .sec-butyl, a /-butyl, a pentyl, an isopentyl, a neopentyl, a /-pentyl, a hexyl, an isohexyl or the like. Also, the alkane moiety of the alkanesulfonyl is a saturated
hydrocarbon corresponding to the above alkyl.
The term "alkoxy" (including the "alkoxy" in a
hydroxyalkylaminoalkoxy, an alkoxycarbonyl, a carbonylalkoxy, a carbonylalkoxyalkyl, and a cyclohexyioxycarbonyloxyalkoxy) stands for a linear or branched alkoxy group having 1 to 6 carbon atoms, and the alkoxy group is preferably, for example, a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a seobutoxy, a t-butoxy, an n-pentyloxy, an «-hexyloxy, or the like.
The term "alkenyl" stands for a linear or branched alkenyl group having 2 to 4 carbon atoms, and the alkenyl group is preferably, for example, a vinyl, an allyl, a propenyl, an isopropenyl, a 1 -butenyl, a 2-butenyl, or the like. The term "halogen" stands for a fluorine, a chlorine, a bromine, an iodine, or the like.
The aminoalkyl (f) of Ri may be substituted with an alkylcarbonyl or an aminocarbonyl, or the aminoalkyl (x) of R3 is substituted with an aminocarbonyl or an alkanesulfonyl, and each substituent thereof is substituted at an amino group moiety of the aminoalkyl.
Among the compounds of the present invention, preferred
compounds are as follows.
2-Cyano-4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzoffjazulene hydrochloride [Compound 1 ]
2-Bromo-4-(l -methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulene hydrobromide [Compound 2]
Ethyl [4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylate [Compound 3]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen- 2-yl]carboxylic acid hydrochloride [Compound 4]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f|azulen- 2- yl]carboxylic acid hydrochloride [Compound 5]
Ethyl 3-[4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]acrylate hydrochloride [Compound 6]
3- [4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]acrylic acid hydrochloride [Compound 7] 2-Bromo-4-( 1 -methylpiperidin-4-ylidene)-4H- 1 -thiabenzo[f]azulene [Compound 8]
2-Cyano-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulene [Compound 9]
2-t-Butoxycarbonylamino-4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro 4H-3-thiabenzo[f]azulene [Compound 10]
2- AcetyIamino-4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H-3-thiabenzo[fJazulene [Compound 1 1]
2- Aminomethyl-4-( 1 -methylpiperidin-4-yl idene)-9, 10-dihydro-4H-3 -thiabenzo[f]azulene dihydrochloride [Compound 12]
2- Acetylaminornethyl-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H
3- thiabenzo[fJazulene hydrochloride [Compound 13]
2-Ureido-4-( 1 -methylpiperidin-4-y I idene)-9, 10-dihydro-4H-3-
thiabenzo f]azulene [Compound 14]
3-[4-( l-Methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulen-2-yl]acrylic acid [Compound 15]
2-/-Butoxycarbonylamino-4-( 1 -methylpiperidin-4-ylidene)-9, 1 Q-dihydro-4H-l -thiabenzo[f]azulene [Compound 16]
2- Acetylamino-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thia-benzo[f]azulene [Compound 17]
2-Ureido-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f)azulene [Compound 18]
2-Aminomethyl-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1- thiabenzo[f|azulene dihydrochloride [Compound 19]
2- Acety laminomethyl-4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 - thiabenzo[f]azulene hydrochloride [Compound 20]
Ethyl [4-( 1 -methy lpiperidin-4- lidene)-9, 10-dihydro-4H-3-thiabenzo[f azulen-2-yl]carboxylate [Compound 21]
Ethyl 3-[4-( l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[fJazulen-2-yl]acrylate [Compound 22]
Ethyl [4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulen-2-yl]acetate hydrochloride [Compound 23]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulen- 2- yl lacetic acid [Compound 24]
6-Cyano-4-( 1 -methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[l]azulene [Compound 25]
[4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]carboxylic acid [Compound 26]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-Hydroxyethy 1) [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxamide) [Compound 27]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N,N-bis(2-hydroxyethyl)amide hydrochloride (IUPAC: N,N-Bis(2-hydroxyethyl) [4-(l-methylpiperidin-4-ylidene)-9, ) 0-dihydro-4H-l-thiabenzo[f)azulen-2-yl]carboxamide hydrochloride)
[Compound 28]
2-(2-Hydroxyethy lamino)ethyl [4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H-l-thiabenzo[f]azulen-2-yl]carboxylate dihydrochloride
[Compound 29]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(3-hydroxypropyl)amide (IUPAC: N-(3-Hydroxypropy I) [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[l]azulen-2-yl]carboxamide) [Compound 30]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yI]carboxylic acid amide (IUPAC: [4-(l -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxamide) [Compound 31 J [4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]acetic acid [Compound 32]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[i]azulen-2-yl]carboxylic acid-N-[2-(piperidin- 1 -yl)ethyl]amide dihydrochloride (IUPAC: N-(2-Piperidin- 1 -yl-ethyl) [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[flazulen-2-y l]carboxamide dihydrochloride)
[Compound 33 ]
Ethyl 3-[4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]acrylate hydrochloride [Compound 34]
3-[4-(l-Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl]acrylic acid [Compound 35]
Ethyl 3-[4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-2-yl]acrylate hydrochloride [Compound 36]
3-[4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]acrylic acid [Compound 37]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-methoxyethyl)amide hydrochloride (IUPAC: N-(2-Methoxyethy l)-[4-( 1 -methylpiperidin-4-ylidene)-9510-dihydro-4H- 1 -thiabenzo[f azulen-2-yl]carboxamide hydrochloride) [Compound 38]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-aminoethyl)amide dihydrochloride (lUPAC: N-(2-Aminoethy 1) [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxamide dihydrochloride) [Compound 39] [4-( 1 -Methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-methoxyamide hydrochloride (IUPAC: N-Methoxy [4-( l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H- l -thiabenzo[l7]azulen-2-yl]carboxamide hydrochloride) [Compound 40]
[4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -lhiabenzo[f|azulen-2-yl]carboxylic acid-N-(carbamoyl)methylamide (IUPAC: N-{ [4-(l -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl] }carbonyl}aminoacetamide) [Compound 41]
»
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl carboxylic acid-N-acetic acid methyl ester amide hydrochloride (I UP AC: Methyl N- { [4-( 1 -methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carbonyl}aminoacetate hydrochloride)
[Compound 42]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen- 2- yljcarboxylic acid morpholine amide hydrochloride (lUPAC: l-{ [4-( l -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f Jazulen-2-yl]carbonyl}mo hoIine hydrochloride) [Compound 43]
Ethyl [4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]carboxylate hydrochloride [Compound 44]
[4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]carboxylic acid [Compound 45]
3- [4-( l -Methylpiperidin-4-ylidene)-4H-3-thiabenzo[ ]azulen-2-yl]acrylic acid [Compound 46]
Ethyl 3-[4-( 1 -methylpiperidin-4-ylidene)- 10-oxo-9, 10-dihydro-4H- 1 -thiabenzo[fjazulen-2-yl]acrylate [Compound 47]
3-[4-( 1 -Methylpiperidin-4-ylidene)- 10-oxo-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]acrylic acid [Compound 48]
2-Ureidomethy l-4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene [Compound 49]
Ethyl [4-( 1 -methylpiperidin-4-y lidene)- 10-oxo-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylate [Compound 50]
[4-( 1 -Methylpiperidin-4-ylidene)- 10-oxo-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid [Compound 51]
3-[4-( 1 -MethyIpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f azulen-2-yl]acry lie acid-N-(2-hydroxyethyl)arnide (IUPAC : N-(2-Hydroxyethyl)-3-[4-(l-methy.lpiperidin-4-ylidene)-9,10-dihydro-4H-3-thiabenzo[f]azulen-2-yl]acrylamide) [Compound 52]
[4-( 1 -Methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3 -thiabenzo[f]azu[en-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide
(IUPAC: N-(2-Hydroxyethyl)-[4-(l-methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]carboxamide) [Compound 53] [4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]acetic acid hydrochloride [Compound 54]
[4-( 1 -Methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3 -thiabenzo[fjazulen-2-yl]carboxylic acid-N-(2-hydroxyethyl)amide
(IUPAC: N-(2-Hydroxyethyl)-{[4-(l -methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl] } carboxamide) [Compound 55] ] 2-[4-(l-Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1-thiabenzo[f|azulen-2-yl]propionic acid hydrochloride [Compound 56] 2- [4-( 1 -Methy lpiperidin-4-y lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl]propionic acid hydrochloride [Compound 57] [4-( 1 -Methy lpiperidin-4-y lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-2-yl]acetic acid hydrochloride [Compound 58]
[4-(l-Methylpiperidin-4-ylidene)-4H-l-thiabenzo[ |azulen-2-yl]acetic acid hydrochloride [Compound 59]
2-[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H-3- thiabenzo[f]azulen-2-yl]propionic acid hydrochloride [Compound 60] Ethyl [4-( 1 -ethoxycarbony lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -
thiabenzo[f]azulen-2-yl]carboxylate [Compound 611
Ethyl [4-(piperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yljcarboxylate [Compound 62]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]acetic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-Hydroxyethyl)-{ [4-( 1 -methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}acetamide) [Compound 63]
2-[4-( 1 -MethyIpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-6-yl]propionic acid-N-(2-hydroxyethyl) amide
(IUPAC : N-(2-Hydroxyethyl)- {2-[4-( 1 -methy lpiperidin-4-y 1 idene)-4, 10-dihydro-9-oxa-3-thiabenzo[fJazulen-6-yl]}propionamide) [Compound 64]
2- Methyl-2-[4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f)azulen-2-yl]propionic acid [Compound 65]
3- [4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl]acrylic acid-N-(2-hydroxyethyl)amide (IUPAC: N-(2-Hydroxyethyl)-{3-[4-(l -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]}acrylamide) [Compound 66]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f|azulen-2-yl]carboxylic acid-N-(2-hydroxyethyl) amide (IUPAC: N-(2-Hydroxyethyl)- { [4-( 1 -methylpiperidin-4-y!idene)-9} 10-dihydro-4H-3 -thiabenzo[t]azulen-2-yl] }carboxamide) [Compound 67]
2-Methyl-2-[4-( l -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fJazulen-6-yl]propionic acid [Compound 68]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-hydroxyethyl)-N-methylamide hydrochloride
(IUPAC: N-(2-Hydroxyethyl)-N-methyl-{[4-( l -methylpiperidin-4-ylidene)-9, 10 -dihydro-4H- 1 -thiabenzo[f|azulen-2-y 1] } carboxamide hydrochloride) [Compound 69]
[4-( 1 -Methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f] azulen-2-yl]carboxylic acid-N-(2-hydroxypropyl) amide (IUPAC: N-(2-Hydroxypropyl)-{ [4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]} carboxamide) [Compound 70]
[4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yI]carboxylic acid-N-(l -hydroxyprop-2-yl)amide (IUPAC: N-( l -Hydroxyprop-2-yl)-{ [4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]} carboxamide) [Compound 71]
[4-( 1 -Methylpiperidin-4-ylidene)-9J 10-dihydro-4H- 1 -thiabenzo[f] azulen-2-yl]carboxylic acid-N-( l ,2-dihydroxypropyl)amide (IUPAC: N-(l ,2-Dihydroxypropy I)- { [4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 72]
] [4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-( l ,3-dihydroxyprop-2-yl)amide (IUPAC : N-( 1 ,3-Dihydroxyprop-2-yl)- { [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-y 1] } carboxamide) [Compound 73]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-hydroxy-N-methylamide (IUPAC: N-Hydroxy-N-methyl-{ [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]} carboxamide) [Compound 74]
2-Ethoxycarbonylamino-4-( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-
4H- l -thiabenzo[f]azulene [Compound 75]
2-Isopropoxycarbonylamino-4-(l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H- l-thiabenzo[f)azulene [Compound 76]
[4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-fluoroethyl)amide (IUPAC: N-(2-Fluoroethyl)-{ [4~( 1 -methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl] }carboxamide) [Compound 77]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azuIen-2-yl]carboxylic acid-N-hydroxyamide (IUPAC: N-Hydroxy-{ [4-( l -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 78]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2,2,2-trifluoroethyl)amide (IUPAC: N-(2,2,2-Trifluoroethyl)- { [4-( 1 -methy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo f]azuIen-2-yl] }carboxamide) [Compound 79]
[4_( i -Methy Ipiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-methyl- l-hydroxyprop-2-yI)amide (IUPAC: N-(2-Methyl- 1 -hydroxyprop-2-yl)-{[4-( I -methyIpiperidin-4-ylidene)-9, 10-dihydro-4H- l-thiabenzo[flazulen-2-yl] }carboxamide) [Compound 80] [4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(3,3,3,2,2-pentafluoropropyl)amide (IUPAC: N-(3,3,3,2,2-Pentafluoropropyl)-{ [4-(l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl] } carboxamide) [Compound 81 ]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid-N-(2-mercaptoethyl)amide (IUPAC: N-(2-
Mercaptoethyl)- { [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yl]}carboxamide) [Compound 82]
[4-(l -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- l-thiabenzo[f]azulen-2-yl]carboxylic acid-N-amino-N-(2-hydroxyethyl)amide (IUPAC: N-Amino-N-(2-hydroxyethyl)-{ [4-( l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H- l -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 83] [4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f)azulen-2-yl]carboxylic acid-N-methyl-N-methoxy amide (IUPAC: N-Methyl-N-methoxy- { [4-( 1 -methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 84]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yl]carboxylic acid-N-propylamide (IUPAC: N-Propyl-{ [4-( l -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 85]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f] azulen-2-yl]carboxylic acid-N-allyl amide (IUPAC: N-Allyl-{[4-( l -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]}carboxamide) [Compound 86]
[4-( i -Methylpiperidin-4-ylidene)- 10-oxo-9, 10-dihydro-4H- 1 -thiabenzo[f)azulen-2-yl]acetic acid [Compound 87]
[4-( 1 -Ethoxycarbonylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yl]carboxylic acid [Compound 88]
[4-(l -Methylpiperidin-4-ylidene)-4H-3-thiabenzo[f]azuIen-2-yl]carboxylic acid [Compound 89]
Ethyl [4-( 1 -acetylpiperidin-4-ylidene)-9, 10-dihy dro-4H- 1 -
thiabenzo[f]azulen-2-yl]carboxylate [Compound 90]
[4-( 1 -Acetylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid [Compound 91]
Ethyl {4-[ 1 -(2-carboxyethy l)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl}carboxylate [Compound 92]
3 - [4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H-3-thiabenzo[f)azulen-2-yl]propionic acid [Compound 93]
{4-[ 1 -(2-Cyanoethyl)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl}carboxylic acid [Compound 94]
Ethyl [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-6-yl]carboxylate [Compound 95]
[4-( 1 -Methylpiperidin-4-yl idene)-9, 10-dihydro-4H- 1 -thiabenzo[f] azulen-6-yl]carboxylic acid [Compound 96]
Ethyl 3-[4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]propionate [Compound 97]
3 -[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]propionic acid [Compound 98]
3-[4-( l-Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azu!en-6-yl]propionic acid piperidinamide hydrochloride (lUPAC : 1 - { 3 - [4-( 1 -Methy lpiperidin-4-y lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl]propionyl}piperidine hydrochloride) [Compound 99]
3-[4-(l -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]propionic acid [Compound 100]
Ethyl {4-[ 1 -(3-pyrrolidylpropyl)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -
thiabenzo[f]azulen-2-yl}carboxylate dihydrochloride [Compound 101] {4-[ l -(3-pyrrolidylpropyl)piperidin-4-ylidene]-9, 10-dihydro-4H- l -thiabenzo[r]azulen-2-yl}carboxylic acid [Compound 102]
Ethyl [4-( 1 -ethy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo| f]azulen-2-yl]carboxylate hydrochloride [Compound 103] 6-(2-Hydroxy methyl)-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene [Compound 104]
Ethyl { 4-[ 1 -(2-hydroxyethyl)piperidin-4-y lidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azuIen-2-yl}carboxylate [Compound 105]
Ethyl [4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-6-yl]acetate hydrochloride [Compound 106]
{4-[ 1 -(2-Hydroxyethy l)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl}carboxylic acid hydrochloride [Compound 107] [4-( 1 -Ethy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]carboxylic acid hydrochloride [Compound 108]
Ethyl {4-{ l -[4-(4-/-butylpheny])-4-oxobutyl]piperidin-4-ylidene}-9, 10-dihydro-4H- l -thiabenzo[f]azulen-2-yl}carboxylate [Compound 109] Ethyl {4-[l -(2-ethoxycarbonylmethoxyethyl)piperidin-4-ylidene]-9, 10-dihydro-4H- l-thiabenzo[f azulen-2-yl}carboxylate hydrochloride
[Compound 1 10]
Ethyl {4-[l -(2-carboxymethoxyethyl)piperidin-4-ylidene]-9, 10-dihydro-4H- l -thiabenzo[f]azulen-2-yl}carboxylate [Compound 1 1 1]
2- Vinyl-4-( 1 -methylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[ Jazulene [Compound 1 12]
Ethyl (4-piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-
thiabenzo[ ]azulen-6-yl)acetate hydrochloride [Compound 1 13]
(4-Piperidin-4-ylidene-4J 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetic acid [Compound 1 14]
Ethyl 4-( l-methylpiperidin-4-ylidene)-9, l 0-dihydro-4H-3-thiabenzo[f|azulene-6-carboxylate [Compound 1 15]
Methyl [4-( 1 -methylpiperidin-4-y lidene)-4, 10-dihydro-9-oxa- 1 -thiabenzo[f]azulen-6-yl]acetate hydrochloride [Compound 1 16]
[4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa- 1 -thiabenzo[F]azulen-6-yl]acetic acid [Compound 1 17]
Methyl {4-[l -(2-hydroxyethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl} acetate hydrochloride [Compound 1 18]
{4-[ 1 -(2-Hydroxyethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl} acetic acid [Compound 1 19]
4- [ 1 -(4-Hydroxybuty l)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene-2-carboxylic acid [Compound 120]
4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3 -thiabenzo [fjazulene- 6-carbox lic acid [Compound 121]
2- {4-[ I -(2-Hydroxyethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}ethanol [Compound 122]
Methyl 4-[4-(l-methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]butyrate hydrochloride [Compound 123]
4-[4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]butyric acid [Compound 124]
3- [4-(6-Carboxymethyl- 10H-9-oxa-3-thiabenzo[f|azulen-4-ylidene)piperidin-l-yl]propionic acid [Compound 125]
Methyl (4-pipendin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo[flazulen-6-yl)acetate hydrochloride [Compound 126]
Methyl [4-( 1 -ethylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]acetate hydrochloride [Compound 127]
[4-(l-Ethylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen- 6-yl]acetic acid [Compound 128]
Meth l [4-( 1 -propylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl]acetate hydrochloride [Compound 129]
[4-( 1 -Propylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]acetic acid [Compound 130]
Methyl [4-( 1 -isopropylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]acetate hydrochloride [Compound 13 1 ]
[4-( 1 -Isopropylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fJazulen-6-yl]acetic acid [Compound 132]
Ethyl 4-( 1 -propy lpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene-2-carboxylate hydrochloride [Compound 133]
4-( 1 -Propylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -lhiabenzo[f |azulene-2-carboxylic acid hydrochloride [Compound 134]
Methyl 4-(4-piperidin-4-y lidene-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl)butyrate hydrochloride [Compound 135]
4-(4-Piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)butyric acid hydrochloride [Compound 136]
Propyl (4-piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate hydrochloride [Compound 137]
Meth l {4- [ 1 -(3-hydroxypropy l)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-
3- thiabenzo[f]azulen-6-yl} acetate hydrochloride [Compound 138] {4-[ l -(3-Hydroxypropyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetic acid [Compound 139]
Ethyl [4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-6-yl]acetate hydrochloride [Compound 140]
Methyl 4-[4-( l -ethylpiperidin-4-ylidene)-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]butyrate hydrochloride [Compound 141 ]
4- [4-( 1 -Ethylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]butyric acid [Compound 142]
Ethyl 3-(4-piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6 yl)acrylate hydrochloride [Compound 143]
3-(4-Piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[f)azulen-6-yl)acrylic acid [Compound 144]
Ethyl 3-(4-piperidin-4-y lidene-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl)acrylate hydrochloride [Compound 145]
3- (4-Piperidin-4-ylidene-9, 10-dihydro-4H-l-thiabenzo[f|azulen-2-yl)acrylic acid [Compound 146]
Ethyl [4-(l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulen-6-yl]acetate hydrochloride [Compound 147]
[4-( 1 -Methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[l]azulen- 6-yl]acetic acid hydrochloride [Compound 148]
Ethyl 4-( 1 -isopropylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulene-2-carboxylate hydrochloride [Compound 149]
4- ( 1 -lsopropylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene-2-carboxylic acid [Compound 150]
[4-( 1 -Methy lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-6-yl]acetic acid [Compound 151]
Ethyl 2-methy l-2-(4-piperidin-4-y lidene-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yl)propionate hydrochloride [Compound 152]
2-Methy l-2-(4-piperidin-4-ylidene-9, 10-dihydro-4H- 1 -thiabenzo[fjazulen-2-yl)propionic acid hydrochloride [Compound 153] Eth l 2-[4-( 1 -ethylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen-2-yl]-2-methyIpropionate hydrochloride
[Compound 154]
2-[4-( 1 -EthyIpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulen- 2- yl]-2-methylpropionic acid [Compound 155]
Methyl 5-[4-( 1 -methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl]valerate hydrochloride [Compound 156]
- [4-( 1 -Methy lpiperidin-4-y lidene)-4t 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl]valeric acid [Compound 157]
Ethyl 3-[4-( 1 -ethy lpiperidin-4- Iidene)-9, 10-dihydro-4H- 1 -thiabenzo[f|azulen-2-yl]acrylate [Compound 158]
3- [4-( 1 -Ethylpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f jazulen-2-yl]acryIic acid hydrochloride [Compound 159]
Ethyl 4-( 1 -ethylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulene-6-carboxylate [Compound 160]
4- (l-Ethylpiperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulene-6-carboxylic acid [Compound 161]
- (4-Piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-6-yl)valeric acid [Compound 162]
Methyl {4-[ l-(3-piperidin-l-yl-propyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl}acetate dihydrochloride [Compound 163] {4- 1 -(3-Piperidin- 1 -yIpropyl)piperidin-4-ylidene]-4, 10~dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}acetic acid [Compound 164]
Methyl [4-( l-methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa~3-thiabenzo[f]azulen-6-yloxy]acetate hydrochloride [Compound 165]
[4-( 1 -Methylpiperidin-4-y lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yloxy]acetic acid [Compound 166]
Methyl {4-[ 1 -(2-oxopropy l)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetate hydrochloride [Compound 167]
{4-[ 1 -(2-Oxopropyl)piperidin-4-yl idene]-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl} acetic acid [Compound 168]
Methyl {4-[ l-(4-oxopentyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}acetate hydrochloride [Compound 169]
{4-[ 1 -(4-Oxopentyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetic acid [Compound 170]
Methyl [4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f)azulen-6-ylsulfanyl]acetate hydrochloride [Compound 171] [4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f)azulen-6-ylsulfanyl]acetic acid [Compound 172]
Ethyl 3-[4-(6-methoxycarbonyImethyl- 10H-9-oxa-3-thiabenzo[fJazulen-4-y]idene)piperidin-l -yl]propionate hydrochloride [Compound 173]
Methyl {4-[ 1 -(2-ureidoethyl)piperidin-4- lidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetate [Compound 174]
{4-[l-(2-Ureidoethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl}acelic acid [Compound 175]
1 -Cyclohexyloxycarbonyloxyethyl 4-( 1 -meth lpiperidin-4-ylidene)-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene-2-carboxylate hydrochloride
[Compound 176]
Methyl {4-[ l -(2-methanesulfonylaminoethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl } acetate hydrochloride
[Compound 177]
{4-[ 1 -(2-Met.hanesulfonylaminoethyl)piperidin-4-ylidene]-4, 1 Q-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetic acid [Compound 178]
f-Butyl 4-(6-carboxymethyl- 10H-9-oxa-3-thiabenzo[fjazulen-4-ylidene)piperidine- l -carboxylate [Compound 179]
1 -Cyclohexyloxycarbonyloxyethyl (4-piperidin-4-ylidene-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate hydrochloride [Compound 180]
Ethyl 4-[ 1 -(2-ethoxyethyl)piperidin-4-y lidene]-9, 10-dihydro-4H- 1 -thiabenzo[f|azulene-2-carboxylate hydrochloride [Compound 181 ]
4-[ 1 -(2-Ethoxyethyl)piperidin-4-ylidene]-9, 10-dihydro-4H- 1 -thiabenzo[f]azulene-2-carboxylic acid [Compound 182]
1 -Methyl-4-[6-(2-piperidin- 1 -ylethyl)- 10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene]piperidine dihydrochloride [Compound 183]
Methyl 4-{4-[ l -(2,3-dihydroxypropyl)piperidin-4-ylidene]-4, I 0-dihydro- 9-oxa-3-thiabenzo[f]azulen-6-yl}butyrate hydrochloride [Compound 184 ]
4- {4-[ 1 -(2.3-Dihydroxypropyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}butyric acid [Compound 185]
3- { 4-[6-(2-Piperidin- 1 -ylethyl)- 10H-9-oxa-3-thiabenzo[i]azulen-4-
ylidene]piperidin-l-yl}propionic acid [Compound 186]
Methyl 4-{4-[ l -(4-oxopentyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}butyrate hydrochloride [Compound 187]
4-{4-[l-(4-Oxopentyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl}butyric acid [Compound 188]
Methyl 2-methy l-2-[4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa- 3-thiabenzo[f]azulen-6-ylsulfanyl]propionate hydrochloride
[Compound 189]
2- Methyl-2-[4-( l-methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-ylsulfanyl]propionic acid hydrochloride
[Compound 190]
Methyl {4-| 1 -(3-oxobutyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl) acetate hydrochloride [Compound 191]
{4-[ l-(3-Oxobutyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} acetic acid [Compound 192]
] Methyl {4-[l-(3-methanesulfonylaminopropyl)piperidin-4-ylidene|- 4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl } acetate hydrochloride
[Compound 193]
{4-[ 1 -(3-Methanesulfonylaminopropyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl}acetic acid [Compound 194]
Methyl 3-{4-[ 1 -(2-methanesulfonylaminoethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-6-yl}propionate hydrochloride
[Compound 195]
3- { 4-[ 1 -(2-Methanesulfonylaminoethyl)piperidin-4-y Iidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl} propionic acid [Compound 196]
Methyl (4-piperidin-4- lidene-4, 10-dihydro-9-oxa-3-thiabenzo[fjazuIen-6 ylsulfanyl)acetate hydrochloride [Compound 197]
Methyl {4-[ l-(3-methylsulfanylpropyl)piperidin-4-ylidene]-4, 10-dihydro- 9-oxa-3-thiabenzo[f]azulen-6-yl} acetate hydrochloride [Compound 198]
{4-[ 1 -(3-Methylsulfanylpropyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3 thiabenzo[f]azulen-6-yl } acetic acid [Compound 199]
Methyl {4-[ l -(2-methylsulfanylethyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f|azulen-6-yl}acetate hydrochloride [Compound 200]
{4-[ 1 -(2-Methylsulfanylethyi)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl} cetic acid [Compound 201 ]
2- Methyl-2-[4-( 1 -propylpiperidin-4-y lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-ylsulfanyl]propionic acid hydrochloride
[Compound 202]
3- (4-Piperidin- 4-ylidene-9, 10-dihydro-4H-3-thiabenzo[t]azulen-2-yl)acrylic acid [Compound 203]
[6-Fluoro-4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]acetic acid [Compound 204]
[6-Chloro-4-( l -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-2-yl]acetic acid [Compound 205]
2-[6-Chloro-4~( 1 -methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]-2-methylpropionic acid [Compound 206]
[6-Methoxy-4-( 1 -methy lpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-2-yl]acetic acid [Compound 207]
[6-Methyl-4-( 1 -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fjazulen-2-yrjacetic acid [Compound 208]
3-(4-Piperidin-4-ylidene-4H- 1 -thiabenzo[f]azulen-2-yl)propionic acid [Compound 209]
3- (4-Piperidin-4-ylidene-4H-3-thiabenzo[fjazulen-2-yl)propionic acid [Compound 210]
4- Piperidin-4-ylidene-9}l0-dihydro-4H-3-thiabenzo[f]azulene-6- carboxylic acid [Compound 21 1]
4-(2-Bromo-9, 10-dihydro- 1 -thiabenzo[f]azulen-4-ylidene)- 1 - methylpiperidine [Compound 212]
[0022] Among the compounds of the present invention, in the above- mentioned general formula (I), a compound in which one of Ri and R2 stands for a hydrogen is preferred, and more preferred compounds include the compounds listed in Tables 18 and 19 set forth later. Further, compounds listed in Table 21 having excellent anti-histamine actions and low brain transfer are especially preferred.
[0023] A general method for producing the compound of the present
invention will be given hereinbelow. The compound of the present invention represented by the above-mentioned general formula (I) can be produced according to the method described below. Here, it is obvious for one of ordinary skill in the art that the exact methods usable in the production of specified compounds can vary depending upon their chemical structures.
[0024] Of the above-mentioned compounds of the present invention
represented by the above-mentioned general formula (I), a 4-(piperidin-4- ylidene)-9f 10-dihydro-4H-l-thiabenzo[f]azulene compound can be produced in accordance with a method described in Japanese Patent Laid-
Open No. Sho-49-69677; a 4-(piperidin-4-ylidene)-4H- 1 -thiabenzo[f]azulene compound can be produced in accordance with methods described in Japanese Patent Laid-Open No. Sho-49-69677 and Helvetica Chimica Acta, 49, Fasc. Emile Cherbuliez (1966) No. 26, 214-234; a 4-(piperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f|azulene compound can be produced in accordance with a method described in Helvetica Chimica Acta, 54, Fasc. 1 (1971), 277-282; a 4-(piperidin-4-ylidene)-4H-3-thiabenzo[f]azulene compound can be produced in accordance with methods described in Japanese Patent Laid-Open No. Sho-49-69677, Helvetica Chimica Acta, 49, Fasc. Emile Cherbuliez ( 1966) No. 26, 214-234, and Helvetica Chimica Acta, 54, Fasc. 1 (1971 ), 277-282; a 4-(piperidin-4-ylidene)-10-oxo-9, 10-dihydro-4H-l-thiabenzo[f azulene compound can be produced in accordance a method described in Helvetica Chimica Acta, 59, Fasc. 3 ( 1976), 866-877; and a 4-(piperidin-4-y lidene)-4, 10-dihydro-9-oxa- 1 -thiabenzo[f]azulene compound and a 4-(piperidin-4- lidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulene compound can be produced in accordance methods described in
WO 2005/00313 1.
] The formation of the functional groups on the aromatic ring can be accomplished by bromination with bromine or NBS (N-bromosuccimide), lithio-formation reaction with an alkyllithium reagent, a Friedel-Crafts acylation reaction, a Vilsmeier formylation reaction, or the like. Further, the brominated compound can be subjected to a carbonylation reaction, a Heck reaction, a cyanation reaction, a formylation reaction, an Ullmann reaction, a Suzuki coupling reaction, or the like, with properly using a
transition metal catalyst such as palladium to introduce a desired functional group. Alternatively, compounds can be synthesized by selecting a starting raw material previously having any substituent at a position corresponding thereto.
] (1) Case where A is unsubstituted
Genera] methods for producing a 4-(piperidin-4-ylidene)-9, 10-dihydro-4H-l -thiabenzo[fJazulene compound, a 4-(piperidin-4-ylidene)-4H- l-thiaben2:o[f]azulene compound, a 4-(piperidin-4-ylidene)-9, 10-dihydro-4H-3-thiabenzo[f]azulene compound, a 4-(piperidin-4-ylidene)-4H-3-thiabenzo[fJazulene compound, a 4-(piperidin-4-ylidene)-4, 10-dihydro-9-oxa-l-thiabenzo[f]azulene compound, and a 4-(piperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulene compound, each of the general formula (II) will be given hereinbelow. The compounds represented by the general formula (II) are obtained by an alkylation reaction, an Ullmann reaction, or a Michael reaction of a compound represented by the general formula (III). For example, an alkylation reaction is earned out with an alkyl halide or the like in a solvent such as acetone, benzene, or DMF (dimethylformamide) at a suitable temperature between room temperature and a boiling point of the solvent, in the presence of a base such as potassium carbonate, sodium hydride, or potassium butoxide.
(Ill) (II)
[0027] The compound represented by the general formula (III) is obtained by an alkali hydrolysis, hydrobromic acid decomposition, or reducing reaction of a compound represented by the general formula (IV). For example, the alkali hydrolysis reaction is carried out by refluxing while heating in a solvent such as butanol or isopropanol, in the presence of a strong base such as sodium hydroxide or potassium hydroxide.
[0028] The compound represented by the general formula (IV) can be synthesized by a carbonylation reaction of a compound represented by the general formula (V). For example, the reaction is carried out by refluxing while heating in a solvent such as benzene or dichloroethane, in the presence of ethyl chloroformate or 2,2,2-trichloroethyl chloroformate.
The compound represented by the general formula (V) can be obtained by subjecting a compound represented by the general formula (VI) to a cyanation reaction, a carbonylation reaction, a Heck reaction, an alkylation reaction, or a formylation reaction with properly using a palladium catalyst, or alternatively converting a compound represented by the general formula (VI) to a boric acid compound and subjecting the compound to a Suzuki coupling reaction. For example, a cyanation reaction can be carried out with a ligand such as DPPF ( Ι , Γ-bis(diphenylphosphino)ferrocene), PPh3 (triphenylphosphine),
P (o-tol)3(tris(2-methylphenyl)phosphine), P(t-Bu)3 (tri-tert-butylphosphine), or N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride, using copper cyanide, zinc cyanide, iron ferrocyanide, or sodium cyanide, in the presence of Pd(dba)2 (palladium(O) bis(dibenzylidene acetone)), Pd;:(dba)3 (dipalladium(O) tris(dibenzylidene acetone)), Pd(OAc)2 (palladium(II) acetate), or Pd(PPh3)4 (palladium(O)
tetrakis(triphenylphosphine)). The reaction can be carried out in a compatible solvent, such as DMF, water, acetone, acetonitrile, toluene, THF (tetrahydrofuran), or a mixture thereof, at a suitable temperature, preferably at a temperature between room temperature and a boiling point of the solvent,
(VI) (V)
33
The compound represented by the general formula (V) can be obtained by subjecting a compound represented by the general formula (VI) to a cyanation reaction, a carbonylation reaction, a Heck reaction, an alkylation reaction, or a formylation reaction with properly using a palladium catalyst, or alternatively converting a compound represented by the general formula (VI) to a boric acid compound and subjecting the compound to a Suzuki coupling reaction. For example, a cyanation reaction can be carried out with a ligand such as DPPF (1,1 '-bis(diphenylphosphino)ferrocene), PPh3 (triphenylphosphine),
P (o-tol)3(tris(2-methylphenyl)phosphine), P(t-Bu)3 (tri-ierr-butylphosphine), or N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride, using copper cyanide, zinc cyanide, iron ferrocyanide, or sodium cyanide, in the presence of Pd(dba)2 (palladium(O) bis(dibenzylidene acetone)), Pcl2(dba)3 (dipalladium(O) tris(dibenzylidene acetone)), Pd(OAc)2 (palladium(II) acetate), or Pd(PPh3)4 (palladium(O)
tetrakis(triphenylphosphine)). The reaction can be carried out in a compatible solvent, such as DMF, water, acetone, acetonitrile, toluene, THF (tetrahydrofuran), or a mixture thereof, at a suitable temperature, preferably at a temperature between room temperature and a boiling point of the solvent.
34
[0030] The compound represented by the general formula (VI) is obtained by bromination of a compound represented by the general formula (VII). As a bromination agent, bromine, NBS or the like can be used. The reaction can be carried out in a compatible solvent such as acetic acid, chloroform, carbon tetrachloride, ethyl acetate, methanol, or a mixture thereof at a suitable temperature, preferably a temperature between 0°C and a boiling point of the solvent.
(VM) (VI)
[0031] The compound represented by the general formula (VII) is obtained by subjecting a product after a Grignard reaction of a compound represented by the general formula (VIII) to a dehydration reaction or a McMurry reaction. For example, a Grignard reaction is carried out by treating a compound represented by the general formula (VIII) with a Grignard reagent prepared from magnesium and 4-chloro-N- methylpiperidine, in a non-aqueous solvent such as THF or toluene at a suitable temperature from a melting point to a boiling point of the solvent. The subsequent dehydration reaction can be carried out with hydrochloric acid, trifluoroacetic acid, thionyl chloride or the like, in the absence of a solvent or in a suitable solvent such as water, ethanol, or dichloromethane, at an optimal reaction temperature from a melting point to a boiling point
of the solvent. The compound represented by the general formula (VIII) can be synthesized in accordance with methods described in Japanese Patent Laid-Open No. Sho-49-69677, Helvetica Chimica Acta, 54, Fasc. 1 ( 1971 ), 277-282, and WO 2005/003 131.
A 4-(piperidin-4-y lidene)- 10-oxo-9, 10-dihydro-4H- 1 - thiazobenzo[f]azulene compound represented by the general formula (IX) is obtained by concurrently subjecting a compound represented by the formula (X) to a hydrolysis reaction of methyl enol ether and a
dehydration reaction of an alcohol. This reaction can be carried out with an inorganic acid such as hydrochloric acid, or an organic acid in a water- containing solvent such as water or ethanol, at a temperature between room temperature and a boiling point.
36
[0033] The compound represented by the general formula (X) can be
obtained by subjecting a compound represented by the general formula (XI) to a cyanation reaction, a carbonylation reaction, a Heck reaction, an alkylation reaction, or a formylation reaction with properly using a palladium catalyst, or converting a compound represented by the general formula (XI) to a boric acid compound and subjecting the compound to a Suzuki coupling reaction. For example, a cyanation reaction can be carried out with a ligand such as DPPF, PPh3, P (o-tol)3, P(t-Bu)3, or Ν,Ν'- (2,6-diisopropylphenyl)dihydroimidazolium chloride, using copper cyanide, zinc cyanide, iron ferrocyanide, or sodium cyanide, in the presence of Pd(dba)2) Pd2(dba)3, Pd(OAc)2, or Pd(PPh3)4. The reaction can be carried out in a compatible solvent, such as DMF, water, acetone, acetonitrile, toluene, THF, or a mixture thereof, at a suitable temperature, preferably at a temperature between room temperature and a boiling point of the solvent.
[0034] The compound represented by the general formula (XI) is obtained by subjecting a compound represented by the general formula (XII) to a Grignard reaction or the like. For example, a Grignard reaction can be carried out by treating a compound represented by the general formula
37
(XII) with a Grignard reagent prepared from magnesium and 4-chloro-N- methylpiperidine, in a non-aqueous solvent such as THF or toluene at a suitable temperature from a melting point to a boiling point of the solvent.
[0035] The compound represented by the general formula (XII) can be obtained by a β-elimination reaction or the like, which is carried out subsequent to subjecting a compound represented by the general formula (XIII) to a methanol decomposition reaction. For example, the methanol decomposition is carried out by refluxing while heating in methanol. The β-elimination reaction can be carried out with a base such as DBU ( 1 ,8- diazabicyclo[5,4,0]und-7-ene), triethylamine, or potassium butoxide, in a solvent such as THF, benzene, toluene, or methanol at a suitable temperature from room temperature to a boiling point of the solvent.
[0036] The compound represented by the general formula (XIII) is
synthesized by subjecting a compound represented by the general formula
38
(XIV) to a bromination reaction or the like with NBS or the like. For example, the bromination reaction is carried out by refluxing while heating using benzoyl peroxide or the like as an initiator in a small amount in an appropriate solvent such as chloroform, carbon tetrachloride,
dichloroethane, or toluene.
(XIV) (XIII)
[0037] The compound represented by the general formula (XIV) is
synthesized by subjecting a compound represented by the general formula (XV) to bromination or the like with bromine. The bromination is carried out in a solvent such as chloroform, acetic acid, or methanol at a suitable temperature from a melting point to a boiling point of the solvent.
(XV) (XIV)
[0038] The compound represented by the general formula (XV) is
synthesized by subjecting a compound represented by the general formula (XVI) to an intramolecular Friedel-Crafts reaction or the like. For example, the intramolecular Friedel-Crafts reaction can be carried by subjecting a carboxylic acid itself, or a product after converting the acid to an acid chloride or a mixed acid anhydride, to a reaction in the presence of,
39
if necessary, a Lewis acid such as polyphosphoric acid, aluminum chloride, titanium chloride, tin chloride, or BF3*OEt2 (boron tri luoride-diethyl ether complex), appropriately using a solvent such as THF, dichloromethane, chloroform, dichloroethane, carbon disulfide, or nitrobenzene, at an optimal temperature between a melting point of the solvent to 300°C.
The compound represented by the general formula (XVI) can be synthesized by subjecting a compound represented by the general formula (XVII) to an Aldol reaction, a Wittig reaction, a Wittig-Horner reaction, a Peterson reaction, or the like. For example, in a case where a Wittig reaction is used, a compound represented by the general formula (XVII) is treated with NBS to brominate a methyl group, and then treated with triphenylphosphine to form a phosphonium salt. At this time, a
bromination reaction is carried out by refluxing while heating using benzoyl peroxide or the like as a reaction initiator in a small amount, in a solvent such as carbon tetrachloride or dichloroethane. The reaction of benzyl bromide obtained by the bromination reaction with
triphenylphosphine is carried out by heating in a solvent such as benzene, toluene, or dichloroethane. The resulting phosphonium salt can be converted to a compound represented by the formula (XVI) by treating the phosphonium salt with a base such as butoxypossium or sodium hydride to
40
form an ylide, condensing the ylide with thiophene aldehyde, and finally reducing a double bond of the condensate. At this time, the treatment of the phosphonium salt with thiophene aldehyde is carried out in a solvent such as THF, acetonitrile, benzene, or toluene, at a suitable temperature from a melting point to a boiling point of the solvent. The reduction of a double bond of a product from a Wittig reaction is carried out by contact reduction, catalytic hydrogen migration reaction, or hydrazine reduction using a palladium catalyst or a Wilkinson complex.
The compounds represented by the general formula (I) mentioned above embrace, in a case where a pharmaceutically acceptable salt thereof is present, various kinds of salts thereof, and include, for example, addition salts with an acid such as hydrochloric acid, oxalic acid, fumaric acid, p-toluenesulfo ic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, or nitric acid. In addition, the salts of carboxyl group of the compounds include suitable alkali metal salt of sodium, potassium, calcium and the like. These salts can be produced from each compound in a free form, or converted reversibly, in accordance with a known method. In addition, in a case where the compounds are present in the state of a steric isomer such as a cis-trans isomer, an optical isomer or a coordination isomer, or a hydrate or a metal complex compound, the
41
present invention embraces any of steric isomers, hydrates, and complex compounds.
[0041] The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent to form a medicament. Also, the compound can be produced into preparations by any ordinary methods, and the compounds can be produced into formulations as an orally administered agent such as a tablet, a capsule, a fine powder, or a liquid, or as a parenterally administered agent for subcutaneous administration, intramuscular administration, intrarectal administration, or intranasal administration. In the prescription, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, and the compounds can be used alone or in a proper combination, and further, a blending agent with another pharmaceutically active ingredient.
[0042] The orally administered preparation can be used directly, or in a proper combination with a suitable additive, for example, a conventional excipient such as lactose, mannitol, corn starch, or potato starch, together with a binder such as a crystalline cellulose, a cellulose derivative, gum arabic, corn starch, or gelatin, a disintegrant such as corn starch, potato starch, carboxymethyl cellulose potassium, a lubricant such as talc or magnesium stearate, and other additive such as a filler, a wetting agent, a buffer, a preservative, or perfume, and the like to produce a tablet, a powder, a granule, or a capsule.
[0043] In addition, the compound can be produced into preparations in a dosage form other than above that is optimal for the treatment depending upon the kinds of the disease and the patients, including, for example,
42
externally administered agents, such as injections, suppositories, inhalants, aerosols, syrups, instillations, and ointments, and the like.
[0044] The desired dose for the compound of the present invention may vary depending upon the subject to be administered, the dose form, the administration method, the administration time period, and the like, In order to obtain a desired effect, the compound of the present invention can be generally orally administered in an amount of from 0.5 to 1000 mg, and preferably from 1 to 500, for adult, at once or in several divided
administrations per day. In the case of the parenteral administration (for example, an injection), the daily dose is preferably from one-third to one- tenth the dose level for each of the doses mentioned above.
EXAMPLES
[0045] Next, the present invention will be specifically described
hereinbelow by the Examples, without intending to limit the scope of the present invention thereto.
A melting point was determined by placing a sample in a glass capillary tube, and using Yamato Scientific, Model MP-21, a melting point measuring instrument (No compensation of the thermometer was made). The MS spectrum was measured with POLARIS Q (Thermo Quest). Ή- NMR was measured with Bruker, Model ARX500, a nuclear magnetic resonance analyzer, in which chemical shift was expressed in ppm, using TMS added as an internal standard (6 = 0 ppm) as a standard. Silica gel column chromatography was performed using silica gel BW- 127ZH for chromatography (FUJI SILYSIA CHEMICAL LTD.). Thin-layer
43
chromatography was performed using silica gel F254 (Merck, No. 5715), in which detection was made using a UV lamp and a 5% phosphomolybdic acid-ethanol color development reagent.
[0046] Example 1.
Production of 4-f 2-Bromo-9.10-dihydro- 1 -thiabenzol flazulen-4-ylideneV 1 -methylpiperidine [Compound 2121
Bromine (1.0 mL, 19.5 mmol) was added dropwise to a chloroform (50 mL) solution of 4-(9,l 0-dihydro- l-thiabenzo[f]azulen-4-ylidene)-l- methylpiperidine (5.76 g, 19.5 mmol) at 0°C, and the mixture was stirred at room temperature for 2 hours. Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and an organic layer was separated. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform-methanol = 9: 1), to give 5.6 g (91%) of the captioned compound in the form of white crystals.
p. 14Γ- 142°α MS (EI): m/z 375 [M++2], 373 [M+], 1H-NMR
(DMSO-d6) δ: 1.90-2.79 (m, 13H), 3.18-3.22 (m, 2H), 6.85 (s, 1 H), 6.98- 7.30 (m, 4H).
[0047] Example 2.
Production of 4-f 2-Cyano-9, 10-dihvdro- 1 -thiabenzorflazulen-4-ylidene)- 1 -methylpiperidine hydrochloride [Compound 1]
Zn(CN)2 (0.94 g, 8.8 mmol), Pd2(dba)3 (0.61 g, 0.74 mmol), and DPPF (0.89 g, 1.8 mmol) were added to a DMF (25 mL) solution of the compound obtained in Example 1 (5.0 g, 14.7 mmol) in an argon
44
atmosphere, and the mixture was stirred overnight at 80°C. Insoluble matters were filtered off, a saturated sodium chloride solution (50 mL) was then added to the filtrate, and the product was extracted with ethyl acetate. The solvents were distilled off under a reduced pressure, the residue was then purified by silica gel column chromatography (chloroform-methanol = 9:1), and the resulting oily product was treated with 4 mol/L hydrogen chloride-dioxane, to give 1.9 g (40%) of the captioned compound in the form of crystals.
[0048] Example 3.
Production of 4-( 1 -Methylpiperidin-4-y lidene)-9, 10-dihydro-4H- 1 - thiabenzoff|azulene-2-carboxylic acid hydrochloride [Compound 4]
A 2 mol/L aqueous sodium hydroxide solution (20 mL) was added to an ethanol (10 mL) solution of Compound 1 (1.5 g, 4,2 mmol), and the mixture was stirred overnight while refluxing and heating. Ethanol was distilled off under a reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue. The precipitated crystals were collected by filtration, and sufficiently washed with water. The crystals were dried over phosphorus pentoxide at 50°C under a reduced pressure, to give 0.96 g (67%) of the captioned compound.
[0049] Example 4.
Production of Ethyl 4-( 1 -methylpiperidin-4-ylidene)-9.10-dihvdro-4H- 1 - thiabenzoiflazulene-2-carboxylate [Compound 31
Ethanol (10 mL) was chilled to 0°C, and thionyl chloride (0.24 mL, 0.32 mmol) was added dropwise. Compound 4 (100 mg, 0.29 mmol) was added to the solution, and the mixture was stirred for 30 minutes, and then
45
refluxed while heating for 2 hours. After allowing the refluxed mixture to cool in the air, the solvents were distilled off under a reduced pressure, and the precipitated crystals were separated by filtration and dried, to give 107 mg (100%) of the captioned compound in the form of white crystals.
[0050] Example 5.
Production oJ'Ethyl F4-( 1 -ethoxycarbonylpiperidin-4-ylidene)-9, 10- dihydro-4H- l-thiabenzo[f|azulen-2-yl]carboxylate [Compound 611
Ethyl chlorocarbonate (57 mL, 599 mmol) was added to a dichloroethane (140 mL) solution of Compound 3 (22.0 g, 59.9 mmol), and the mixture was stirred overnight while refluxing and healing. The solvent was distilled off under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform), to give 26.3 g (100%) of the captioned compound.
[0051] Example 6.
Production of Ethyl f4-piperidin-4-ylidene)-9.10-dihydro-4H-l- thiabenzorflazulen-2-yl1carboxylate iCompound 621
A 33%) hydrogen bromide-acetic acid solution (23 mL, 133.2 mmol) was added to an acetic acid (90 mL) solution of Compound 61 (10.5 g, 24.7 mmol), and the mixture was refluxed with heating for 5 hours. After allowing the mixture to cool in the air, the solvents were distilled off under a reduced pressure, and the precipitated crystals were separated by filtration and dried to give 8.8 g (82%>) of the captioned compound.
[0052] Example 7.
Production of Ethyl (4-( l-[4-(4- -butylphenvn-4-oxobutyl |piperidin-4- ylidene)-9J0-dihydro-4H-l-thiabenzo[flazulen-2-yllcarboxylate
46
I Compound 109]
Triethylamine (2.1 mL, 15.1 mmol) and l -(4-/erf-butylphenyl)-4- chlorobutan- l -one ( 1.98 g, 8.3 mmol) were added to a DMF (75 mL) solution of Compound 62 (3.0 g, 6.9 mmol), and the mixture was stirred at 80°C for 21 hours. The solvents were distilled off under a reduced pressure, water was then added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane- elhyl acetate), to give 0.9 g (23%) of the captioned compound.
[0053] Example 8.
Production o 2-Bromo-4-( 1 -methylpiperidin-4-ylidene)-9.10-dihvdro-4H- 3-thiabenzoff]azulene hydrobromide [Compound 21
Bromine (0,52 mL, 10.2 mmol) was added dropwise to a chloroform (30 mL) solution of 4-(l-methylpiperidin-4-ylidene)-9, 10-dihydro-4H-3- thiabenzo[f]azulene (3.0 g, 10.2 mmol) at 0°C. The mixture was stirred at room temperature for 2 days, and a saturated aqueous sodium bicarbonate solution was then added thereto to allow separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was then purified by column chromatography (chloroform-methanol = 9: 1), to give 3.8 g ( 100%) of the captioned compound in the form of white crystals.
[0054] Example 9.
47
Production of Ethyl 3-f 4-f 1 -methylpiperidin-4-ylideneV9.10-dihvdro-4H-3-thiabenzoff|azulen-2-yl]acrylate fCompound 22]
Triethylamine (35.5 mL, 255 mmol), ethyl acrylate (26.8 mL, 246 mmol), palladium acetate (0.4 g, 1.8 mmol), and tri(o-toluyl)phosphine (1.5 g, 5.0 mmol) were added to a DMF (160 mL) solution of Compound 2 (9.2 g, 24.5 mmol), and the mixture was stirred overnight at 80°C in an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was then washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the resulting residue was then purified by column chromatography (chloroform-methanol = 9: 1 ), to give 7.6 g (79%) of the captioned compound in the form of white crystals.
Example 10.
Production of 4-(6-Bromo- 10H-9-oxa-3-thiabenzorf lazulen-4-ylideneV 1 -methylpiperidine
6-Bromo- 10H-9-oxa-3-thiabenzo[f]azulen-4-one (21.6 g, 100 mmol) was added to a Grignard reagent prepared from 4-chloro-N-methylpiperidine (20 mL, 150 mmol), a metal magnesium (3.6 g, 150 mmol), dibromoethane (0.1 mL), and THF (200 mL). The reaction mixture was stirred at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the solution to stop the reaction, and a product was then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced
48
pressure, the resulting residue was dissolved in dichloromethane (300 mL), trifluoroacetic acid (77 mL, 1.0 mol) was added thereto, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the resulting residue was then purified by column chromatography (hexane-ethyl acetate = 3 :2), to give 16.2 g (81%) of the captioned compound.
MS (EI): m/z 378.0 [M++l]. Ή-NMR (DMSO-d6) δ: 2.09-2.77 (m, 1 1 H), 4.85 (d, J = 15.5 Hz, 1 H), 5.42 (d, J = 15.5 Hz, 1H), 6.81-7.45 (m, 5H).
Example 1 1 .
Production of 2-Γ4-( 1 -Methy lpiperidin-4-y lidene>4, 10-dihvdro-9-oxa-3-thiabenzorflazulen-6-yllpropionic acid hydrochloride [Compound 57]
Hexarnethyldisilazane (5.0 mL, 31.2 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L butyllithium-hexane solution ( 19.5 mL, 31 .2 mmol) was added dropwise thereto. After stirring the mixture for 30 minutes, t-butyl propionate (2.1 g, 16.1 mmol) was added dropwise to the solution, and stirred for 30 minutes. Further, Pd(dba)2 (0.45 g, 0.8 mmol) and N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride (0.34 g, 0.8 mmol) were added thereto, the mixture was stirred for 10 minutes, and a toluene (25 mL) solution of 4-(6-bromo- 10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)-l-methylpiperidine (3.0 g, 8.0 mmol) was then added dropwise thereto. The mixture was stirred overnight at room
49
temperature, water was then added to the reaction mixture, and the product was extracted with ethyl acetate. The solvents in the organic layer were distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The purified compound was dissolved in dioxane (10 mL), a 4 mol/L hydrogen chloride-dioxane solution (12.5 mL, 50 mmol) was added to the solution, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and the precipitated crystals were collected by filtration, to give 1.5 g (69%) of the captioned compound.
[0057] Example 12.
Production of 2-Bromo-9J0-dihydro-l-thiabenzolf|azulen-4-one
Bromine (8.5 mL, 165 mmol) was added dropwise to a chloroform (300 mL) solution of 9,10-dihydro-l-thiabenzo[f]azulen-4-one (23.2 g, 108 mmol), and the mixture was stirred for 4 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, the organic layer was then washed with a saturated aqueous sodium
bicarbonate solution and with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by silica gel
chromatography (hexane-ethyl acetate), to give 22.0 g (69%) of the captioned compound.
MS (El): m/z 294 [M++2], 292 [M+]. Ή-NMR (DMSO-d6) δ: 3.19 (s, 4H), 7.38-7.42 (m, 2H), 7.52-7.55 (m, 2H), 7.78-7.79 (m, 1H).
[0058] Example 13.
Production of 2,9.10-Tribromo-9, 10-dihydro- 1 -thiabenzol |azulen-4-one
50
NBS (65.4 g, 367 mmol) and benzoyl peroxide (0.1 g, 0.5 mmol) were added to a dichloroethane (500 mL) solution of the compound obtained in Example 12 (53,9 g, 184 mmol), and the mixture was refluxed while heating for 4 hours. The reaction mixture was allowed to cool in the air, and a saturated potassium carbonate was then added thereto to allow an organic layer to separate. The organic layer was further washed with a saturated potassium carbonate and with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), to give 76.8 g (93%) of the captioned compound.
Ή-NMR (DMSO-d6) δ: 5.96 (d, J = 5.3 Hz, 1 H), 6.22 (d, J = 5.3 Hz, 1H), 7.67-7.74 (m, 4H), 8.03-8.05 (m, 1H).
Example 14.
Production of 2-Bromo- 10-methoxy- 1 -thiabenzof flazulen-4-one
A methanol (1 100 mL) solution of the compound obtained in
Example 13 (90.2 g, 200 mmol) was refluxed while heating overnight. After allowing the mixture to cool in the air, DBU (63.4 g, 417 mmol) was further added thereto, and the mixture was refluxed while heating for another overnight. The reaction mixture was allowed to cool in the air, and the precipitated crystals were separated by filtration and dried, to give the captioned compound in an amount of 55.7 g, 173 mmol (2 steps, 87%). MS (EI): m/z 322 [M++2], 320 [M+]. Ή-NMR (DMSO-d6) 6: 4.02 (s, 3H), 6.98 (s, 1H), 7.61-7.62 (m, 1 H), 7.77-7.80 (m, 1H), 7.90-7.96 (m, 2H), 8.46-8.47 (m, 1H).
51
[0060] Example 15.
Production of 2-Bromo- 10-methoxy-4-( 1 -methylpiperidin-4-vD-4H- 1 - thiazobenzo[f1azulen-4-ol
The compound obtained in Example 14 (4.27 g, 13.3 mmol) was added to a Grignard reagent prepared from 4-chloro-N-methylpiperidine (2.7 mL, 20 mmol), a metal magnesium (0.49 g, 21 mmol), dibromoethane (0.2 mL), arid THF (20 mL). The reaction mixture was stirred at room temperature for 2 hours, and a saturated aqueous ammonium chloride solution was added to the solution to stop the reaction, and a formed product was then extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), to give 2.8 g (50%) of the captioned compound.
MS (EI): m/z 422 [M++3], 420 [M++l]. Ή-NMR (DMSO-d6) δ: 0.41- 0.43 (ni, 1H), 0.77-0.87 (m, 2H), 1.18-1.52 (m, 3H), 1.83-1.92 (m, 1H), 1.99 (s, 3H), 2.50-2.55 (m, 1 H), 2.64-2.66 (m, 1H), 5.83 (s, 1H), 6.40 (s, 1H), 7.22-7.26 (m, 2H), 7.31-7.34 (m, 1H), 7.38-7.39 (m, 1H), 7.72-7.73 (m, 1H).
[0061] Example 16.
Production of Ethyl [4-hydroxy- 10-methoxy-4-( 1 -methylpiperidin-4-y P- 4H- 1 -thiabenzo f1azulen-2-yl1acetate
Hexamethyldisilazane (16.8 g, 104 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L butyllithium-hexane solution (65 mL,
52
104 mmol) was added dropwise thereto. After stirring the mixture for 30 minutes, ethyl acetate (5 mL, 51 mmol) was added dropwise to the solution, and the mixture was stirred 30 minutes. Further, Pd(dba)2 ( 1.5 g, 2.6 mmol) and N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride (1.1 g, 2.6 mmol) were added to the mixture, the mixture was stirred for 10 minutes, and a toluene (100 mL) solution of the compound obtained in Example 15 (5.0 g, 12 mmol) was then added dropwise thereto. After the mixture was stirred at room temperature overnight, water was added to the reaction mixture, and the product was extracted with ethyl acetate. The solvents in the organic layer were distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography
(hexane-ethyl acetate), to give 3.1 g (60%) of the captioned compound. MS (EI): m/z 428 [M++l]. 1H-NMR (DMSO-d6) δ: 0.41-0.78 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 1.30-1 .83 (m, 5H), 1.99 (s, 3H), 2.50-2.63 (m, 2H), 3.84-3.92 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 5.68 (s, 1H), 6.33 (s, 1H), 7.1 (s, 1H), 7.20-7.74 (m, 4H).
] Example 17.
Production of Γ4-( 1 -Methylpiperidin-4-ylidene)- 10-oxo-9, 10-dihvdro-4H- l -thiabenzorflazulen-2-v 11 acetic acid [Compound 871
Hydrochloric acid (8 mL) was added to an ethanol (24 mL) solution of the compound obtained in Example 16 (2.0 g, 4.7 mmol), and the mixture was refluxed while heating overnight. The solvents were distilled off, water (20 mL) and sodium hydroxide (0.8 g, 20 mmol) were then added to the residue, and the mixture was stirred at room temperature overnight. The property of the solution is adjusted to a pH of 6.5 with
53
hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 0.68 g (39%) of the captioned compound.
[0063] Example 18.
Production of Ethyl (4-HydroxyphenylsulfanvOacetate
Ethyl bromoacetate (21 ,5 mL, 194 mmol) and potassium carbonate (50.7 g, 367 mmol) were added to a DMF (450 mL) solution of 4- mercaptophenol (23.1 g, 183 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5: 1 ), to give 30.3 g (78%) of the captioned compound.
MS (El): m/z 212 [M+]. Ή-NM (DMSO-d6) δ: 1 .1 1 (1, J = 7.1 Hz, 3H), 3.60 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 6.72-6.74 (m, 2H), 7.25-7.27 (m, 2H), 9.64 (s, 1H).
[0064] Example 19.
Production of Methyl 3-(4- ethoxycarbonylmethylsulfanylphenoxymethyl)thiophene-2-carboxylate
Methyl 3-bromomethylthiophene-2-carboxylate (28.2 ml, 120 mmol) and potassium carbonate (36.6 g, 264 mmol) were added to a DMF (300 mL) solution of the compound obtained in Example 18 (28.1 g, 132 mmol), and the mixture was stirred overnight at room temperature. The solvents were distilled off under a reduced pressure, water was added to
54
the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate = 5: 1), to give 35.1 g (80%) of the captioned compound.
1H-NMR (DMSO-d6) δ: 1.1 1 (t, J = 7.1 Hz, 3H), 3.70 (s, 2H), 3.83 (s, 3H), 4.04 (q, J = 7.1 Hz, 2H), 5.41 (s, 2H), 6.96-7.38 (m, 5H), 7.89-7.90 (m, 1H).
[0065] Example 20.
Production of 3-(4-Carboxymethylsulfanylphenoxymethvnthiophene-2- carboxylic acid
An aqueous sodium hydroxide ( 1 .2 g, 480 mmol) solution was added to a methanol (250 mL) solution of the compound obtained in Example 19 (35.1 g, 96 mmol), and the mixture was refluxed while heating for 2 hours. After allowing the mixture to cool in the air, the solvents were distilled off under a reduced pressure, and water was added to the residue. The solution was neutralized with hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 30.0 g (97%) of the captioned compound.
Ή-NMR (DMSO-d6) 6: 3.64 (s, 2H), 5.41 (s, 2H), 6.94-7.36 (m, 5H), 7.79-7.80 (m, 1H), 13.04 (brs, 2H).
[0066] Example 21.
Production of (4-Oxo-4,10-dihydro-9-oxa-3-thiabenzorflazulen-6- ylsulfanvPacetic acid
55
Trifluoroacetic acid anhydride (28.0 mL, 201 mmol) was added to a dichloroethane (300 mL) solution of the compound obtained in Example 20 (29.0 g, 89 mmol), and the mixture was stirred overnight at 60°C. The solvents were distilled off under a reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration and dried, to give 26.7 g (98%) of the captioned compound.
MS (EI): m/z 307 [M++l]. Ή-NMR (DMSO-d6) δ: 3.81 (s, 2H), 5 ,31 (s, 2H), 7.20-8.10 (m, 5H), 12.78 (brs, 1H).
[0067] Example 22.
Production of Methyl (4-oxo-4.10-dihvdro-9-oxa-3-thiabenzoiflazulen-6- ylsulfanyPacetate
Methyl iodide (6.5 mL, 104 mmol) and potassium
hydrogencarbonate ( 17.0 g, 170 mmol) were added to a DMF (200 mL) solution of the compound obtained in Example 21 (26.1 g, 85 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate = 5: 1), to give 24.0 g (88%) of the captioned compound.
MS (EI): m/z 320 [M+]. Ή-NMR (DMSO-d6) 5: 3.64 (s, 3H), 3.91 (s, 2H), 5.31 (s, 2H), 7.20-7.27 (m, 2H),7.63-7.66 (m, 1H), 7.97-8.10 (m, 2H).
[0068] Example 23.
56
Production of Methyl [4-hvdroxy-4-( 1 -methylpiperidin-4-v0-4, 10-dihydro-9-oxa-3-thiabenzo fiazulen-6-ylsulfanyr]acetate
A Grignard reagent prepared from magnesium (2.8 g, 1 16 mmol 4-chloro-l -methylpiperidine (15.5 mL, 1 16 mmol), and THF (180 mL) was ice-cooled, and a THF (120 mL) solution of the compound obtained in Example 22 (18.5 g, 58 mmol) was added dropwise thereto. After allowing the mixture to react for 30 minutes, a saturated ammonium chloride was added thereto, and a product was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated ammonium chloride and with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate = 3:2), to give 4.4 g (18%) of the captioned compound.
Ή-NMR (DMSO-d6) δ: 0.78-0.80 (m, 1H), 1.34- 1.64 (m, 5Η), 2.05 (s, 3Η), 2.26-2.29 (m, 1H), 2.63-2.75 (m, 2Η), 3.61 (s, 3H), 3.80-3.87 (m, 2H), 4.74 (d, J = 15.5 Hz, III), 5.38 (d, J = 15.5 Hz, l H), 6.06 (s, I H), 6.70-6.71 (m, IH), 7.09-7.48 (m, 4H).
] Example 24.
Production of Methyl \4-( 1 -methyrpiperidin-4-ylV4, 10-dihvdro-9-oxa-3-thiabenzo[ f]azulen-6-ylsulfanyl1acetate
Trifluoroacetic acid (10 mL) was added to a dichloromethane solution of the compound obtained in Example 23 (5.7 g, 14 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off, and the residue was purified by silica gel column
57
chromatography (hexane:ethyl acetate = 3:2), to give a free compound. Thereafter, 4 mol/L hydrogen chloride-dioxane (8.0 mL, 32 mmol) was added thereto, and the mixture was stirred for 1 hour. The solvents were distilled off under a reduced pressure, and ether was added to the residue to allow crystallization. The precipitated crystals were separated by filtration and dried, to give 4.1 g (69%) of the captioned compound.
Mp. 210°-212°C. Ή-NMR (DMSO-d6) δ: 2.36-3.60 (m, 1 1H), 3.60 (s, 3H), 3.81-3.93 (m, 2H), 4.87 (d, J = 15.3 Hz, 1H), 5.45 (d, J = 15.3 Hz, 1H), 6.85-7.53 (m, 5H), 10.67 (brs, 1H).
Example 25.
Production of [4-( 1 -Methyl piperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-ylsulfanvHacetic acid [Compound 172]
An aqueous sodium hydroxide (1.4 g, 680 mmol) solution was added to an ethanol (40 mL) solution of the compound obtained in
Example 24 (2.9 g, 6.7 mmol), and the mixture was refluxed while heating for 2 hours. After allowing the mixture to cool in the air, the solvents were distilled off under a reduced pressure, water was added to the residue, and the mixture was neutralized with hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.3 g (50%) of the captioned compound.
] Example 26.
Production of 1-Cyclohexyloxycarbonyloxyethyl 4-( l-methylpiperidin-4-ylidene -9.10-dihvdro-4H-l-thiabenzo[f)azulene-2-carboxylate
hydrochloride [Compound 1761
Triethylamine (6.2 mL, 44.2 mmol), potassium iodide (4.4 g, 26.5
58
mmol), and 1-chloroethyl cyclohexyl carbonate (2.2 g, 10.6 mmol) were added to a DMF (50 mL) solution of the compound 4 (3.0 g, 8.84 mmol), and the mixture was stirred at 80°C overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduce pressure. The residue was purified by silica gel column chromatography
(hexane:ethyl acetate = 5: 1). The resulting free amino acids were dissolved in dioxane (20 mL), 4 mol/L hydrogen chloride-dioxane was added thereto, and the mixture was stirred for 1 hour. The solvents were distilled off under a reduced pressure, and ether was added thereto to allow crystallization of a hydrochloride. The crystals were separated by filtration and dried, to give 1.8 g (2 steps, 37%) of the captioned
compound.
] Example 27.
Production of 4-(2-Bromo- 10H-9-oxa-3-thiabenzoiflazulen-4-ylidene)- 1 -methyl-piperidine
Bromine (5 mL, 98 mmol) was added dropwise to a chloroform (300 mL) solution of l-methyl-4-(10H-9-oxa-3-thiabenzo} fJazulen-4-ylidene)piperidine ( 19.3 g, 65.0 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution was then added thereto to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled
59
off under a reduced pressure, and the residue was purified by column chromatography (chloroform .methanol = 9: 1). The crystals were formed from a petroleum ether, to give 1 1.2 g (46%) of the captioned compound. Mp. 10 - 103 °C. Ή-NMR (CDC13) 2.10-2.71 (m, 1 1H), 4.76 (d, J = 15.4 Hz, 1 H), 5.36 (d, J = 15.4 Hz, 1 H), 6.93 (s, 1 H), 7.08-7.12 (m, 3H), 7.26- 7.29 (m, 1 H).
Example 28.
Production of f-Butyl [4-(l-methylpiperidin-4-ylidene)-4,10-dihydro-9-oxa-3-thiabenzorflazulen-2-yllacetate
Hexamethyldisilazane (1 1.97 g, 74.2 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L n-butyllithium-hexane solution (46.6 mL, 74.6 mmol) was added dropwise thereto. t-Butyl acetate (4,9 mL, 36.7 mmol) was added dropwise to the solution, and the mixture was stirred for 30 minutes. Pd(dba)2 (1.05 g, 1.8 mmol), N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride (0.80 g, 1 .9 mmol), and the compound obtained in Example 27 (7.0 g, 18.6 mmol) were added thereto, and the mixture was heated to room temperature, and stirred overnight. Water was added to the reaction mixture, and the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer was distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate = 9: 1), to give 3.30 g (43%) of the captioned compound in the form of an oily product.
MS (EI): m/z 412 [M++l]. 1H-NMR (DMSO-d6) δ: 1.40 (s, 9H), 2.1 1 -2.28 (m, 6H), 2.39-2.57 (m, 3H), 2.68-2.74 (m, 2H), 3.70 (s, 2H), 4.76 (d, J =
60
.4 Hz, 1H), 5.36 (d, J = 15.4 Hz, 1H), 6.58 (s, 1H), 7.05-7.10 (m, 3H), 7.25 (dd, J = 2.3, 8.5 Hz, 1H).
[0074] Example 29.
Production of [4-( 1 -Methylpiperidin-4-ylidene)-4, 10-dihvdro-9-oxa-3- thiabenzorflazulen-2-yllacetic acid hydrochloride rCompound 581
A 4 mol/L hydrogen chloride-dioxane solution (10 mL, equivalent to 40 mmol hydrogen chloride) was added to a dioxane (30 mL) solution of the compound obtained in Example 28 (2.21 g, 5.4 mmol), and the mixture was stirred at 40°C for 8 hours. The solvents were distilled off under a reduced pressure, and the precipitated crystals were collected by filtration, to give 1.70 g (81%) of the caption compound in the form of crystals containing 0.5 equivalents of dioxane.
[0075] Example 30.
Production of Methyl (4-[ 1 -(4-oxopentvQpiperidin-4-ylidene]-4, 10- dihvdro-9-oxa-3-thiabenzo[f|azulen-6-yl)acetate
-Chloro-2-pentanone (2.4 mL, 20.9 mmol) was added to a DMF (50 mL) solution of methyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3- thiabenzo[f|azulen-6-yl)acetate (2.50 g, 7.0 mmol), anhydrous potassium carbonate (2.15 g, 15.6 mmol), and potassium iodide (1.41 g, 8.5 mmol), and the mixture was stirred overnight at 80°C. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvents were then distilled off under a reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 19: 1), to give 2.40 g (78%) of the captioned
61
compound in the form of an oily product.
MS (EI): m/z 439 [M+]. Ή-NMR (DMSO-d6) δ: 1.63 (tt, J = 7.1 ,7.1 Hz, 2H), 2.09 (s, 3H), 2.17-2.33 (m, 5H), 2.36-2.47 (m, 3H), 2.49-2.61 (m, 2H), 2.65-2.72 (m, 2H), 3.59 (s, 3H), 3.61 and 3.65 (ABq, J = 15.7 Hz, 2H), 4.82 (d, J = 15.3 Hz, 1H), 5.40 (d, J = 15.3 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 2.0, 8.2 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H).
[0076] Example 31.
Production of (4-Γ 1 -(4-Oxopentyl)piperidin-4-ylidenel-4< 10-dihydro-9- oxa-3-thiabenzo[flazulen-6-yll acetic acid [Compound 1701
A 2 mol/L aqueous sodium hydroxide solution (5 mL, equivalent to 10 mmol sodium hydroxide) was added to an ethanol (20 mL) solution of the compound obtained in Example 30 (2.40 g, 5.5 mmol), and the mixture was stirred at room temperature for 2 hours. The solvents were distilled off, water was then added to the residue, and the aqueous solution was adjusted to a pH of 7 with a diluted hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.30 g(56%) of the captioned compound.
[0077] Example 32.
Production of 2-Methyl-2-[4-f 1 -methy)piperidin-4-ylidene)-4, 10-dihydro- 9-oxa-3-thiabenzo[ilazulen-6-ylsulfanyl |propionic acid hydrochloride
[Compound 901
An aqueous solution (10 mL) of sodium hydroxide (0.82 g, 20.6 mol) was added to an ethanol (20 mL) solution of methyl 2-methyl-2-[4- ( l -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-
62
ylsulfanyl]propionate hydrochloride [Compound 189] (0.88 g, 1.8 mmol), and the mixture was refluxed while heating for 6 hours. The solvents were distilled off under a reduced pressure, the residue was then dissolved in water, the solution was neutralized with a diluted hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 0.67 g (72%) of the captioned compound in the form of crystals.
[0078] Example 33.
Production of Ethyl 4-(2-bromo-9, 10-dihydro- 1 -thia-benzo[ f]azulen-4- ylidene)piperidine- 1 -carboxylate
Ethyl chlorocarbonate (32 mL, 336 mmol) was added to a toluene (200 mL) solution of the compound obtained in Example 1 (21.0 g, 56 mmol), and the mixture was refluxed while heating for 6 hours. The mixture was allowed to cool in the air, and the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate = 19: 1), to give 15.0 g (62%) of the captioned compound in the form of an oily product.
MS (EI): m/z 433 [M++2], 431 [M+]. Ή-NMR (DMSO-d6) δ: 1.17 (t, J = 7.1 Hz, 3H), 2.10-2.23 (m, 2H), 2.38-2.48 (m, 2H), 2.68-2.83 (m, 2H), 2.92-3.26 (m, 4H), 3.52-3.78 (m, 2H)> 4.04 (q, J = 7.1 Hz, 2H), 6.90 (s, 1H), 7.02-7.13 (m, 1H), 7.16-7.36 (m, 3H).
[0079] Example 34.
63
Production of Ethyl 4-[2-(2-ethoxycarbonylvinyl)-9, 10-dihydro- l-thiabenzo|T|azulen-4-ylidene)piperidine- 1 -carboxylate
Ethyl acrylate (18.5 mL, 170 mmol), triethylamine (24 mL, 170 mmol), palladium acetate (0.3 g, 1.3 mmol), and tri(o-toluyl) phosphine (2.0 g, 6.6 mmol) were added to a DMF (50 mL) solution of the compound obtained in Example 33 (8.80 g, 17.0 mmol) in an argon gas stream, and the mixture was stirred overnight at 80°C. The mixture was allowed to cool in the air, water was then added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane-ethyl acetate = 9: 1), to give 6.1 g (79%) of the captioned compound in the form of an oily product.
Ή-NMR (DMSO-d6) δ: 1.18 (t, J = 7.0 Hz, 3H), 1.23 (t, J - 7.0 Hz, 3H), 2.1 1-2.16 (m, 1 H), 2.20-2.28 (m, 1H), 2.38-2.48 (m, 2H), 2.78-2.86 (m, 2H), 2.96-3.14 (m, 1H), 3.20-3.32 (m, 3H), 3.55-3.61 (m, 1H), 3.68-3.74 (m, 1H), 4.04 (q, J = 7.0 Hz, 2H), 4.15 (m, 2H), 6.06 (d, J = 15.7 Hz, 111), 7.03 (d, J = 7.2 Hz, 1H), 7.16-7.24 (m, 2H), 7.27 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 15.7 Hz, 1H).
] Example 35.
Production of t-Butyl 4-r2-(2-ethoxycarbonylethyl)-l-thiabenzol flazulen-4-ylidenelpiperidine- 1 -carboxylate
A 30% hydrogen bromide-acetic acid solution (3.8 mL, equivalent to 67.5 mmol of hydrogen bromide) was added to an acetic acid (50 mL)
64
solution of the compound obtained in Example 34 (6.10 g, 13.5 mmol), and the mixture was stirred at 120°C for 4 hours. The reaction mixture was allowed to cool in the air to room temperature, the residue obtained by distilling the mixture off the solvents under a reduced pressure was dissolved in ethanol (50 mL), a 2 mol/L aqueous sodium hydroxide solution (14 mL, equivalent to 28 mmol sodium hydroxide) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The solvents were distilled off, water was then added to the residue, the aqueous solution was adjusted to a pH of 7 with a diluted hydrochloric acid, and the product was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, the solvents were distilled off under a reduced pressure, di-/-butyl dicarbonate (3.0 g, 13.7 mmol) was then added to a dichloromethane (50 mL) solution of the residue, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, the organic layer was allowed to separate out and dried with anhydrous sodium sulfate, and the solvents were then distilled off under a reduced pressure. Potassium hydrogen carbon ate (4.0 g, 40.5 mmol) and ethyl iodide (1.1 mL, 13.5 mmol) were added to a DM (50 mL) solution of the residue, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the product was extracted with ethyl acetate, the organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 19: 1), to give 2.9 g (45%) of the captioned compound in the form of an
65
oily product,
Ή-NMR (CDCI3) 6: 1.24 (t, J = 7.1 Hz, 3H), 1.45 (s, 9H), 2.08-2.14 (m, IH), 2.20-28 (m, IH), 2.30-2.36 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.84- 3.01 (m, IH), 3.02 (m, I H), 3.12 (t, J = 7.6 Hz, IH), 3.56-3.70 (m, 2H), 4.14 (q, J = 7.1 Hz, IH), 6.59 (s, IH), 6.76 (d, J = 1 1.5 Hz, I H), 6.84 (d, J = 1 1.5 Hz, IH), 7.10 (d, J = 7.6 Hz, IH), 7.23-7.28 (m, I H), 7.31-7.36 (m, 2H).
[0081] Example 36.
Production of Ethyl 3-(4-piperidin-4-ylidene-4H-l-thiabenzo| flazulen-2- vDpropionate
Hydrogen chloride-dioxane (7.5 mL, equivalent to 30 mmol of hydrogen chloride) was added to a dioxane (30 mL) solution of the compound obtained in Example 35 (2.9 g, 6.0 mmol), and the mixture was stirred at room temperature for 5 hours. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform-methanol = 19: 1), to give 2.0 g (88%) of the captioned compound in the form of an oily product.
Ή-NMR (DMSO-d6) 6: 1.15 (t, J = 7, 1 Hz, 3H), 1.82- 1.89 (m, IH), 2.03- 2.10 (m, IH), 2.1 1-2.18 (m, IH), 2.26-2.32 (m, IH), 2.44-2.58 (m, IH), 2.60-2.68 (m, 2H), 2.70-2.82 (m, IH), 3.02 (t, J = 7.3 Hz, 2H), 3.44-3.52 (m, IH), 3.65-3.74 (m, IH), 4.04 (q, J = 7.1 Hz, 2H), 6.67 (s, IH), 6.85 (d, J = 1 1.5 Hz, IH), 6.89 (d, J = 1 1.5 Hz, IH), 7.09 (d, J = 7.5 Hz, IH), 7.25- 7.30 (m, IH), 7.34-7.38 (m, 2H).
[0082] Example 37.
Production of 3-(4-Piperidin-4-ylidene-4H- 1 -thiabenzo[flazulen-2-
66
yDpropionic acid [Compound 209]
A 2 mol/L aqueous sodium hydroxide solution (10 mL, equivalent to 20 mmol of sodium hydroxide) was added to an ethanol (30 mL) solution of the compound obtained in Example 36 (2.0 g, 5.3 mmol), and the mixture was stirred at room temperature for 2 hours. The solvents were distilled off, water was then added to the residue, and the mixture was adjusted to a pH of 7 with a diluted hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.1 g (59%) of the captioned compound.
Compounds of the present invention other than those mentioned above were produced in the same manner in accordance with the general production methods mentioned above and the methods described in Examples, using an appropriate starting raw material in place of the starting raw material in Examples. The data of the properties for the compounds of the present invention thus obtained are shown in Tables 1 through 17.
67 ] [Table 1]
68 5] [Table 2]
69 6] [Table 3]
70 7] [Table 4]
71 8] [Table 5]
72 9] [Table 6j
73 90] [Table 7]
74 91] [Table 8]
75 2] [Table 9]
76 3] [Table 10]
77 4] [Table 1 1]
78 5] [Table 12]
79 6] [Table 13]
80 7] [Table 14]
81 [Table 15]
82 9] [Table 16]
83 0] [Table 17]
84
[0101] Example 38.
In vitro Human Histamine H I Receptor Binding Experiment
Recombinant human histamine HI receptor plasmid (prepared by Invitrogen) was transfected to HEK293A cells with Lipofectamine 2000 (manufactured by Invitrogen). Cells stably expressing human histamine H I receptor were screened with Geneticin (manufactured by Invitrogen), The cells were continued to be cultured using a Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum, 0.1 mmol/L MEM Non- Essential Amino Acids Solution, 2 mmol L L-glutamine and 0.7 mg/mL Geneticin in a 5% C02 incubator at 37°C. The cells stably expressing human histamine H I receptor were prepared using 50 mmol/L Tris-HCl (pH 7.5) (hereinafter referred to as buffer) containing 0.1 % bovine serum albumin, so as to have a concentration of 3* 106 cells/mL, to give a cell sample preparation. Fifty microliters of the buffer, 50 \L of a test substance solution at various concentrations, and 50 L of [ H]pyrilamine solution (final concentration: 3 nmol/L) were added to each of the wells on the 96-well plate, and stirred, and 100 μΐ of the cell sample preparation was then added thereto (at a concentration of 3 * 105 cells/well) to initiate the reaction.
[0102] The cells were incubated at room temperature for 60 minutes, and then filtered on UniFilter GF/C plate (manufactured by Packard) immersed in 0.5% polyethyleneimine using a cell harvester (IH-1 10, manufactured by INNOTECH CORPORATION), to stop the reaction, and the plate was washed with the buffer. The plate after washing was sufficiently dried, and 20 μL· of a scintillator (MaxiLight, manufactured by Hidex) was added
85
thereto, and count per minute (cpm) was measured with a multi-labeled microplate reader (Plate Chameleo II, manufactured by Hidex). The nonspecific binding was cpm in a case where 30 μιηοΙ/L pyrilamine was added. The experiments were carried out at n = 3, and at least repeated 3 times.
One example of the results are shown in Table 18. The compounds of the present invention showed very high potent activity in in vitro human histamine HI receptor binding experiment.
[Table 18]
86
87
[0104] Example 39.
Rat Histamine-Induced Vascular Hyperpermeability Reaction (in Vivo Antihistamine Action)
An SD male rat (SPF) of 180 g in weight was previously fed for one week or more by allowing the rat to take a solid feed and tap water ad libitum, under the environment setting of a temperature of 22°C, humidity of 55% and an artificial illumination of 12 hours a day (light phase 8 am to 8 pm), and the rat was fasted overnight to be used for the experiment. Histamine»dihydrochloride (hereinafter referred to as histamine) and Evans Blue were used by dissolving each in physiological saline upon use. A substance to be tested was dissolved in water for injection or suspended in 0.5% carboxymethyl cellulose sodium, and the rat was orally administered with the solution or suspension (dose volume: 5 mL/kg body weight). After 1 hour from the administration, the physiological saline and the histamine solution were each intracutaneously injected to two locations (20 μg/ .05 ml/location) each on a back part of the rat of which hair was sheared with an electric clipper while anesthetizing with an ether. A 0.5% Evans Blue-containing physiological saline was injected intravenously to the tail of the rat (1 mL / 200 g body weight) immediately before the intracutaneous injection of the histamine.
[0105] After 30 minutes, the animal was decapitated, and allowed to bleed lethally, and the skin was removed to measure an amount of leaked pigment in the blue-stained portion. The measurement of the amount of leaked pigment was carried out as follows. Skins of the pigment leaking site were cut out at two locations, 1 mL of a 2 mol/L aqueous potassium
88
hydroxide solution was added thereto in a test tube, and the test tube was allowed to stand overnight at 37°C to dissolve. Thereafter, 6 mL of a 1 :3 mixed solution of 0.67 mol L phosphoric acid and acetone was added to the solution, and the mixture was vigorously shaken for 10 minutes. Thereafter, the mixture was filtered, and the absorbance of the filtrate at 620 nm was measured. The absorbance obtained from the two locations of the sites injected with physiological saline, as blank value, was used for a compensation. The amount of leaked pigment was calculated from the calibration curve of Evans Blue at 620 nm.
One example of the results is shown in Table 19. The compound of the present invention showed a very potent antagonistic activity in the rat histamine-induced vascular hyperpermeability reaction.
] [Table 19]
89
90
[0107] Example 40.
Murine Cerebral H 1 Receptor Occupying Content (ex vivo)
A 6-week-old ICR male mouse was previously fed for one week or more by allowing the mouse to take a solid feed and tap water ad libitum, under the environment setting of a temperature of 22°C, humidity of 55% and an artificial illumination of 12 hours a day, and the mouse was fasted overnight to be used for the experiment, A substance to be tested was dissolved with water for injection or suspended in 0.5% carboxymethyl cellulose solution, and the solution or suspension was orally administered to the mouse (dose volume: 0.1 mL/10 g body weight). After 1 hour from the oral administration, the mouse was decapitated, and the entire brain, except for cerebellum and medulla oblongatae, was rapidly excised. The excised brain tissue was homogenized with Polytron (manufactured by Kinematica) in an ice-cooled 50 mmol/L phosphate buffered saline (pH 7.4, 100 mg/1.9 mL).
[0108] To a test tube for reaction (TPX-Tube) were added 180 of the brain homogenate, and 10 ΐ^ of 3H-pyrilamine solution (final
concentration: 2 nmol/L) and 10 μί of a non-labeled pyrilamine
solution (final concentration: 200 μηιοΙ/L) or a 50 mmol/L phosphate buffered saline, and the mixture was incubated at room temperature for
45 minutes, and 2.0 mL of an ice-cooled, 50 mmol/L phosphate buffered saline was then added thereto to stop the reaction. The reaction mixture was filtered with a GF/B filter (manufactured by ADVANTEC), and the filtrate was placed in a vial and dried overnight at 60 degrees. After drying, 10 mL of a scintillator (AL-1, toluene-based, manufactured by DOJINDO
91
LABORATORIES) was added to the product, and the disintegration per minute (dpm) was measured with a liquid scintillation counter
(manufactured by Packard, U.S.A., TRI-CARB 2700TR) (5 minutes/vial).
[0109] One example of the results is shown in Table 20. In this experiment, the compound of the present invention require a high concentration for occupying the receptor in the brain, showing that the brain transfer is low. It was evident from the results that the compounds of the present invention show peripheral-selective anti-histamine action without undergoing brain transfer, so that the compounds can alleviate side effects on the central nervous system, such as drowsiness.
[0110] [Table 20]
92
93
[0111] From the results of Examples 39 and 40 mentioned above, the values obtained by dividing the ID50 (Table 20) of the cerebral receptor binding test by the ED50 (Table 19) of the histamine-induced vascular
hyperpermeability reaction test are shown in Table 21. The larger the ID50 (Table 20) of the cerebral receptor binding test, the lower the brain transfer, i.e. the smaller the side effects on the central nervous system, such as drowsiness; and the smaller the ED50 (Table 19) of the histamine-induced vascular hyperpermeability reaction test, the more potent the antihistamine action. Therefore, the value calculated by ID50 ÷ ED50 can serve as an index showing that the larger the calculated value, the more potent the antihistamine action and the smaller the side effects on the central nervous system, such as drowsiness. As shown in Table 21, the compound of the present invention shows a large value for a value calculated by 1D50 ÷ ED50, as compared to an already existing antihistamine Ketotifen. Therefore, it can be said that the compound of the present invention has desired properties as a pharmaceutical composition, especially as an active ingredient for antihistamine, that has a potent antihistamine action and smaller side effects on the central nervous system, such as drowsiness.
[ 01 12] [Table 21]
94
95
INDUSTRIAL APPLICABILITY
The piperidine derivative of the present invention had a potent histamine HI receptor binding ability as shown in Table 18, and showed a potent histamine receptor antagonistic activity in the rat histamine-induced vascular hyperpermeability reaction, as shown in Table 19. Further, as is clear from Table 20, the piperidine derivative shows a low brain transfer even in a cerebral receptor binding test where a mouse is orally
administered, so that the piperidine derivative of the present invention is preferable from the aspect of alleviating side effects on the central nervous system, such as drowsiness. As is clear from the values of Table 21 for together evaluating both of these histamine receptor antagonistic activity and brain transfer, the piperidine derivative of the present invention is a potent histamine receptor antagonistic substance, and has smaller side effects on the central nervous system, such as drowsiness; therefore, the piperidine derivative has properties suitable for an active ingredient of a pharmaceutical composition, such as a desired antihistamine, so that the piperidine derivative is highly useful.
Claims (18)
1. A piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable, wherein the piperidine derivative is represented by the following general formula (I): wherein Rj stands for a hydrogen or a substituent selected from the following (a) to (i): (a) a cyano, (b) acrylic acid (including an alkyl ester and a hydroxyalkylamide), (c) a ureido, (d) an alkenyl, (e) an aminoalkyl which may be substituted with an alkylcarbonyl or an aminocarbonyl, (f) a carbonylalkyl substituted with a hydroxy, an alkoxy or a hydroxy alkyl amino, (g) a carbonyl substituted with a hydroxy, a morpholino, an alkoxy, a hydroxyalkylaminoalkoxy or cyclohexyloxycarbonyloxyalkoxy, (h) a carbonylamino substituted with an alkyl or an alkoxy, 97 (i) an aminocarbonyl which may be substituted with one or two substituents selected from an amino, a hydroxy, an alkoxy, an alkenyl, and an alkyl (which may be substituted with a halogen, a thiol, a piperidino, an amino, an alkoxy, an alkoxycarbonyl, an aminocarbonyl, or one or two hydroxys); and R2 stands for a hydrogen or a substituent selected from the following (j) to (r): (j) a cyano, (k) acrylic acid (including an alkyl ester and a hydroxyalkylamide), (1) an alkyl substituted with a hydroxy or a piperidino, (m) a carbonylalkyl substituted with a hydroxy, an alkoxy (which may be substituted with a cyclohexyloxycarbonyloxy), a piperidino, or a hydroxyalkylamino, (n) a carbonyl substituted with a hydroxy, an alkoxy, or a hydroxyalkylamino, (o) a carbonylalkoxy substituted with a hydroxy or an alkoxy, (p) a carbonylalkylsulfanyl substituted with a hydroxy or an alkoxy, (q) an alkoxy, (r) a halogen; and R3 stands for a hydrogen or a substituent selected from the following (s) to (w): (s) an alkyl which may be substituted with a carboxy, a cyano, a pyrrolidyl, a piperidino, an alkoxy, an alkylsulfanyl, or one or two hydroxys, (t) a carbonyl substituted with an alkyl or alkoxy, (u) a carbonylalkoxyalkyl substituted with a hydroxy or an alkoxy, (v) a carbonylalkyl substituted with an alkyl, an alkoxy, or an 98 alkylphenyl, (w) an aminoalkyl substituted with an aminocarbonyl or an a!kanesulfonyl, wherein one of the above R| and R2 stands for a substituent other than a hydrogen, A stands for unsubstituted or an oxo, B stands for a carbon or an oxygen, one of X and Y stands for a carbon and the other is a sulfur, a broken line part stands for a single bond or a double bond, with proviso that when R2 stands for a halogen or an alkoxy, A is unsubstituted, R] stands for a substituent other than a hydrogen, and B stands for an oxygen.
2. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 1 , wherein A is unsubstituted.
3. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 2, wherein one of Rj and R2 is a carbonylalkyi substituted with a hydroxy, and the other is a hydrogen.
4. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 3, wherein R) is a carbonylalkyi substituted with a hydroxy.
5. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 3, wherein R2 is a carbonylalkyi substituted with a hydroxy.
6. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 2, wherein B is an oxygenA R| is a hydrogen, and R2 is a carbonylalkylsulfanyl substituted with a hydroxy.
7. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 4, wherein B is a carbon. 99
8. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 3, wherein B is an oxygen.
9. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 7, wherein R3 is a hydrogen.
10. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 8, wherein R3 is an unsubstituted alkyl.
1 1 . The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 8, wherein R3 is an alkylcarbonylalkyl.
12. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 1 , wherein the piperidine derivative represented by the general formula ( 1 ) is [4-( l-methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiazobenzo[f]azulen-2-yl]acetic acid.
13. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 1 , wherein the piperidine derivative represented by the general formula (1) is {4-| T -(4-oxopentyl)piperidin-4-ylidene]-4, 10-dihydro-9-oxa-3-thiabenzo[f azulen-6-yl}acetic acid.
14. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 1 , wherein the piperidine derivative represented by the general formula (1 ) is 2-methyl-2-[4-( l -methylpiperidin-4-ylidene)-4, 10-dihydro-9-oxa-3-thiabenzo[fJazulen-6-ylsulfanyljpropionic acid.
15. The piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to claim 1 , wherein the piperidine 100 derivative represented by the general formula (1) is 3-(4-piperidin-4-ylidene-4H-1 -thiabenzo[fjazulen-2-yl)propionic acid.
16. A pharmaceutical composition comprising at least one member selected from the piperidine derivatives, and salt and hydrate thereof that are pharmaceutically acceptable as defined in any one of claims 1 to 15.
17. An antihistamine comprising at least one member selected from the piperidine derivatives, and salt and hydrate thereof that are pharmaceutically acceptable as defined in any one of claims 1 to 15.
18. Use of the piperidine derivative, and salt and hydrate thereof that are pharmaceutically acceptable according to any one of claims 1 to 15, in the manufacture of a medicament for the treatment of at least one disease selected from bronchial asthma, allergic rhinitis, pollinosis, urticaria, and atopic dermatitis. FOR THE APPLICANT Dr, Yitzhak Hess & Partners
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| WO2011013632A1 (en) * | 2009-07-28 | 2011-02-03 | 日本臓器製薬株式会社 | Method for producing thiabenzoazulene propionic acid derivative |
| JP5460620B2 (en) * | 2010-01-29 | 2014-04-02 | 日本臓器製薬株式会社 | Pharmaceutical containing aminopropylidene derivative |
| CN113880808A (en) * | 2020-07-03 | 2022-01-04 | 合肥医工医药股份有限公司 | Triazole compounds, preparation method and medical application thereof |
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| US3491103A (en) | 1963-12-19 | 1970-01-20 | Sandoz Ag | Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes |
| FR1437412A (en) | 1963-12-19 | 1966-05-06 | Sandoz Sa | New benzo-cyclohepta-thiophenes and their preparation |
| US3464983A (en) | 1964-02-04 | 1969-09-02 | Sandoz Ag | 4h-benzo(4,5)cyclohepta(1,2-b)thiophenes |
| FR1502857A (en) * | 1965-10-01 | 1967-11-24 | Sandoz Sa | New derivatives of benzo-cyclohepta-thiophene and their preparation |
| DK127072A (en) * | 1967-02-17 | |||
| CH531000A (en) | 1970-03-11 | 1972-11-30 | Sandoz Ag | Process for the preparation of new benzocycloheptathiophenes |
| SU512711A3 (en) | 1970-03-11 | 1976-04-30 | Сандос Аг (Фирма) | Method for preparing benzo (4,5) -cyclohepta (1,2-b) -thiophene derivatives |
| IL37621A (en) | 1970-09-24 | 1975-05-22 | Sandoz Ag | Benzocycloheptathiophene derivatives,their preparation and pharmaceutical compositions containing them |
| CH568312A5 (en) | 1972-01-24 | 1975-10-31 | Sandoz Ag | |
| BE794377A (en) | 1972-01-24 | 1973-07-23 | Sandoz Sa | NEW DERIVATIVES OF BENZO-CYCLOHEPTA-THIOPHENE |
| US3960894A (en) * | 1972-01-24 | 1976-06-01 | Sandoz Ltd. | 9-Bromo-or chloro-9,10-dihydro-10-dihydro-10-alkoxy-4H-benzo[4,5]cyclo-hepta[1,2-b]thiophen-4-ones |
| SE388858B (en) * | 1972-09-20 | 1976-10-18 | Sandoz Ag | ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW 2-ALKYL-4 (1-ALKYL-4-PIPERIDYLIDENE) BENZOCYCLOHEPTATIOFENDER DERIVATIVES |
| DE2605980A1 (en) | 1975-02-26 | 1976-09-09 | Sandoz Ag | NEW BENZOCYCLOHEPTATHIOPHEN DERIVATIVES, THEIR PRODUCTION AND USE |
| DE2626583A1 (en) * | 1975-06-24 | 1977-01-13 | Sandoz Ag | NEW BENZOCYCLOHEPTATHIOPHEN DERIVATIVES THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS |
| DE3170504D1 (en) | 1980-09-02 | 1985-06-20 | Sandoz Ag | Piperidylidene derivatives, their production and pharmaceutical compositions containing them |
| JPS5760351A (en) | 1980-09-29 | 1982-04-12 | Mitsubishi Electric Corp | Multicolor picture forming apparatus by electrostatic recording system |
| FR2620121B1 (en) | 1987-09-09 | 1990-01-05 | Synthelabo | ((PYRIMIDINYL-2) -AMINOALKYL) -1 PIPERIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| CA1341370C (en) | 1988-04-28 | 2002-06-18 | John J. Powinski | Fused polycyclic compounds, methods of manufacture, and their use as paf antagonists, antihistamines and/or antiinflammatory agents |
| JPH03294277A (en) | 1990-04-11 | 1991-12-25 | Hokuriku Seiyaku Co Ltd | Piperidine derivative |
| CA2038417A1 (en) | 1990-04-11 | 1991-10-12 | Yasuo Ito | Piperidine compounds, method for preparation thereof, and a pharmaceutical composition comprising the same |
| GB9102997D0 (en) | 1991-02-13 | 1991-03-27 | Pfizer Ltd | Therapeutic agents |
| DE69833748T2 (en) | 1997-04-03 | 2006-11-23 | Bridge Pharma, Inc., Sarasota | BENZOCYCLOHEPTHA-THIOPHEN COMPOUNDS |
| RU2279428C2 (en) * | 2000-09-18 | 2006-07-10 | Эйсай Ко., Лтд. | Derivatives of pyridazinone and triazinone and their using as pharmaceutical preparations |
| CA2530444C (en) | 2003-06-27 | 2012-03-13 | Janssen Pharmaceutica, N.V. | Tricyclic .delta. opioid modulators |
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- 2008-11-20 RU RU2010136055/04A patent/RU2475485C2/en not_active IP Right Cessation
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- 2008-11-20 DK DK08871767.3T patent/DK2243778T3/en active
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- 2008-11-20 MX MX2010008400A patent/MX2010008400A/en not_active Application Discontinuation
- 2008-11-20 CN CN2008801259482A patent/CN101932575B/en not_active Expired - Fee Related
- 2008-11-20 US US12/864,878 patent/US8377967B2/en active Active
- 2008-11-20 JP JP2009551400A patent/JP5096500B2/en active Active
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| HK1152525A1 (en) | 2012-03-02 |
| NZ587050A (en) | 2012-08-31 |
| DK2243778T3 (en) | 2014-11-17 |
| JP5096500B2 (en) | 2012-12-12 |
| US20100331365A1 (en) | 2010-12-30 |
| CN101932575A (en) | 2010-12-29 |
| KR101379783B1 (en) | 2014-03-31 |
| ES2527588T3 (en) | 2015-01-27 |
| AU2008349239A1 (en) | 2009-08-06 |
| AU2008349239B2 (en) | 2012-12-06 |
| WO2009096080A1 (en) | 2009-08-06 |
| EP2243778A4 (en) | 2011-06-08 |
| KR20100114525A (en) | 2010-10-25 |
| CA2713293A1 (en) | 2009-08-06 |
| EP2243778B1 (en) | 2014-10-29 |
| TW200932741A (en) | 2009-08-01 |
| TWI429641B (en) | 2014-03-11 |
| IL207315A0 (en) | 2010-12-30 |
| RU2475485C2 (en) | 2013-02-20 |
| JPWO2009096080A1 (en) | 2011-05-26 |
| US8377967B2 (en) | 2013-02-19 |
| EP2243778A1 (en) | 2010-10-27 |
| CN101932575B (en) | 2013-06-12 |
| MX2010008400A (en) | 2010-08-23 |
| RU2010136055A (en) | 2012-03-10 |
| BRPI0821909A2 (en) | 2018-07-17 |
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